2w2m - Revision history

OCA at 15:41, 13 December 2023

OCA — Wed, 13 Dec 2023 15:41:44 GMT

←Older revision		Revision as of 15:41, 13 December 2023
Line 3:		Line 3:
	<StructureSection load='2w2m' size='340' side='right'caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='2w2m' size='340' side='right'caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W2M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W2M FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.4Å</td></tr>
-	<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat"><~~div style~~='~~overflow~~: ~~auto; max-height: 3em;~~'>[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</~~div~~></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [https://pdbe.org/2w2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [https://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [https://pdbe.org/2w2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [https://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[https://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[https://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[https://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref> <ref>PMID:2569482</ref> <ref>PMID:3955657</ref> <ref>PMID:8347689</ref> <ref>PMID:2318961</ref> <ref>PMID:1446662</ref> <ref>PMID:1867200</ref> <ref>PMID:8462973</ref> <ref>PMID:8168830</ref> <ref>PMID:2726768</ref> <ref>PMID:1464748</ref> <ref>PMID:7573037</ref> <ref>PMID:7583548</ref> <ref>PMID:7550239</ref> <ref>PMID:7635461</ref> <ref>PMID:7635482</ref> <ref>PMID:7649546</ref> <ref>PMID:7649549</ref> <ref>PMID:8740918</ref> <ref>PMID:8664907</ref> <ref>PMID:9026534</ref> <ref>PMID:9254862</ref> <ref>PMID:9143924</ref> <ref>PMID:9259195</ref> <ref>PMID:9104431</ref> <ref>PMID:9654205</ref> <ref>PMID:9452094</ref> <ref>PMID:9452095</ref> <ref>PMID:9452118</ref> <ref>PMID:10206683</ref> <ref>PMID:10660340</ref> [:]<ref>PMID:9852677</ref> <ref>PMID:9678702</ref> <ref>PMID:10422803</ref> <ref>PMID:10090484</ref> <ref>PMID:10447263</ref> <ref>PMID:10978268</ref> <ref>PMID:10980548</ref> <ref>PMID:10882754</ref> <ref>PMID:11298688</ref> <ref>PMID:17142622</ref> <ref>PMID:19319977</ref> <ref>PMID:22160468</ref>	+	[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[https://omim.org/entry/603776 603776]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref> [[https://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.	+	[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 39:		Line 39:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Baysarowich, J]]	+	[[Category: Baysarowich J]]
-	[[Category: Bottomley~~, M J~~]]	+	[[Category: Bottomley MJ]]
-	[[Category: Calzetta, A]]	+	[[Category: Calzetta A]]
-	[[Category: Carfi, A]]	+	[[Category: Carfi A]]
-	[[Category: Cirillo, A]]	+	[[Category: Cirillo A]]
-	[[Category: Cubbon~~, R M~~]]	+	[[Category: Cubbon RM]]
-	[[Category: Cummings, R T]]	+	[[Category: Cummings RT]]
-	[[Category: Fisher~~, T S~~]]	+	[[Category: De Francesco R]]
-	[[Category: ~~Francesco, R De~~]]	+	[[Category: Fisher TS]]
-	[[Category: Mattu, M]]	+	[[Category: Lo Surdo P]]
-	[[Category: Noto, A]]	+	[[Category: Mattu M]]
-	[[Category: Orsatti, L]]	+	[[Category: Noto A]]
-	[[Category: Ruggeri, L]]	+	[[Category: Orsatti L]]
-	[[Category: Santoro~~, J C~~]]	+	[[Category: Ruggeri L]]
-	[[Category: Sitlani, A]]	+	[[Category: Santoro JC]]
-	[[Category: Sparrow~~, C P]]~~	+	[[Category: Sitlani A]]
-	~~[[Category: Surdo, P Lo~~]]	+	[[Category: Sparrow CP]]
-	[[Category: Talamo, F]]	+	[[Category: Talamo F]]
-	~~[[Category: Cardiovascular disease]]~~	+
-	~~[[Category: Familial hypercholesterolemia]]~~	+
-	~~[[Category: Hydrolase-receptor complex]]~~	+
-	~~[[Category: Lipid metabolism]]~~	+
-	~~[[Category: Lipid transport]]~~	+
-	~~[[Category: Serine protease]]~~	+
-	~~[[Category: Steroid metabolism~~]]	+

OCA at 11:51, 30 March 2022

OCA — Wed, 30 Mar 2022 11:51:40 GMT

OCA at 08:51, 25 June 2020

OCA — Thu, 25 Jun 2020 08:51:28 GMT

←Older revision		Revision as of 08:51, 25 June 2020
Line 1:		Line 1:

	==WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR==		==WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR==
-	<StructureSection load='2w2m' size='340' side='right' caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='2w2m' size='340' side='right'caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2W2M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2W2M FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://pdbe.org/2w2m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://pdbe.org/2w2m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 40:		Line 40:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Baysarowich, J]]		[[Category: Baysarowich, J]]
	[[Category: Bottomley, M J]]		[[Category: Bottomley, M J]]

OCA at 20:43, 19 September 2018

OCA — Wed, 19 Sep 2018 20:43:05 GMT

←Older revision		Revision as of 20:43, 19 September 2018
Line 1:		Line 1:
		+
	==WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR==		==WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR==
	<StructureSection load='2w2m' size='340' side='right' caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='2w2m' size='340' side='right' caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://pdbe.org/2w2m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://pdbe.org/2w2m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 15:		Line 16:
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w2/2w2m_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w2/2w2m_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>

OCA at 18:33, 9 February 2016

OCA — Tue, 09 Feb 2016 18:33:10 GMT

←Older revision		Revision as of 18:33, 9 February 2016
Line 2:		Line 2:
	<StructureSection load='2w2m' size='340' side='right' caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='2w2m' size='340' side='right' caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W2M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W2M FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://pdbe.org/2w2m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 19:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2w2m ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 29:		Line 29:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 2w2m" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 37:		Line 38:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Baysarowich, J]]		[[Category: Baysarowich, J]]
	[[Category: Bottomley, M J]]		[[Category: Bottomley, M J]]

OCA at 17:27, 19 January 2015

OCA — Mon, 19 Jan 2015 17:27:29 GMT

←Older revision		Revision as of 17:27, 19 January 2015
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W2M FirstGlance]. <br>		<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W2M FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum]</span></td></tr>
-	<table>	+	</table>
	== Disease ==		== Disease ==
	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[http://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref> <ref>PMID:2569482</ref> <ref>PMID:3955657</ref> <ref>PMID:8347689</ref> <ref>PMID:2318961</ref> <ref>PMID:1446662</ref> <ref>PMID:1867200</ref> <ref>PMID:8462973</ref> <ref>PMID:8168830</ref> <ref>PMID:2726768</ref> <ref>PMID:1464748</ref> <ref>PMID:7573037</ref> <ref>PMID:7583548</ref> <ref>PMID:7550239</ref> <ref>PMID:7635461</ref> <ref>PMID:7635482</ref> <ref>PMID:7649546</ref> <ref>PMID:7649549</ref> <ref>PMID:8740918</ref> <ref>PMID:8664907</ref> <ref>PMID:9026534</ref> <ref>PMID:9254862</ref> <ref>PMID:9143924</ref> <ref>PMID:9259195</ref> <ref>PMID:9104431</ref> <ref>PMID:9654205</ref> <ref>PMID:9452094</ref> <ref>PMID:9452095</ref> <ref>PMID:9452118</ref> <ref>PMID:10206683</ref> <ref>PMID:10660340</ref> [:]<ref>PMID:9852677</ref> <ref>PMID:9678702</ref> <ref>PMID:10422803</ref> <ref>PMID:10090484</ref> <ref>PMID:10447263</ref> <ref>PMID:10978268</ref> <ref>PMID:10980548</ref> <ref>PMID:10882754</ref> <ref>PMID:11298688</ref> <ref>PMID:17142622</ref> <ref>PMID:19319977</ref> <ref>PMID:22160468</ref>		[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[http://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref> <ref>PMID:2569482</ref> <ref>PMID:3955657</ref> <ref>PMID:8347689</ref> <ref>PMID:2318961</ref> <ref>PMID:1446662</ref> <ref>PMID:1867200</ref> <ref>PMID:8462973</ref> <ref>PMID:8168830</ref> <ref>PMID:2726768</ref> <ref>PMID:1464748</ref> <ref>PMID:7573037</ref> <ref>PMID:7583548</ref> <ref>PMID:7550239</ref> <ref>PMID:7635461</ref> <ref>PMID:7635482</ref> <ref>PMID:7649546</ref> <ref>PMID:7649549</ref> <ref>PMID:8740918</ref> <ref>PMID:8664907</ref> <ref>PMID:9026534</ref> <ref>PMID:9254862</ref> <ref>PMID:9143924</ref> <ref>PMID:9259195</ref> <ref>PMID:9104431</ref> <ref>PMID:9654205</ref> <ref>PMID:9452094</ref> <ref>PMID:9452095</ref> <ref>PMID:9452118</ref> <ref>PMID:10206683</ref> <ref>PMID:10660340</ref> [:]<ref>PMID:9852677</ref> <ref>PMID:9678702</ref> <ref>PMID:10422803</ref> <ref>PMID:10090484</ref> <ref>PMID:10447263</ref> <ref>PMID:10978268</ref> <ref>PMID:10980548</ref> <ref>PMID:10882754</ref> <ref>PMID:11298688</ref> <ref>PMID:17142622</ref> <ref>PMID:19319977</ref> <ref>PMID:22160468</ref>
Line 38:		Line 38:
	</StructureSection>		</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Baysarowich, J.]]	+	[[Category: Baysarowich, J]]
-	[[Category: Bottomley, M J.]]	+	[[Category: Bottomley, M J]]
-	[[Category: Calzetta, A.]]	+	[[Category: Calzetta, A]]
-	[[Category: Carfi, A.]]	+	[[Category: Carfi, A]]
-	[[Category: Cirillo, A.]]	+	[[Category: Cirillo, A]]
-	[[Category: Cubbon, R M.]]	+	[[Category: Cubbon, R M]]
-	[[Category: Cummings, R T.]]	+	[[Category: Cummings, R T]]
-	[[Category: Fisher, T S.]]	+	[[Category: Fisher, T S]]
-	[[Category: Francesco, R De.]]	+	[[Category: Francesco, R De]]
-	[[Category: Mattu, M.]]	+	[[Category: Mattu, M]]
-	[[Category: Noto, A.]]	+	[[Category: Noto, A]]
-	[[Category: Orsatti, L.]]	+	[[Category: Orsatti, L]]
-	[[Category: Ruggeri, L.]]	+	[[Category: Ruggeri, L]]
-	[[Category: Santoro, J C.]]	+	[[Category: Santoro, J C]]
-	[[Category: Sitlani, A.]]	+	[[Category: Sitlani, A]]
-	[[Category: Sparrow, C P.]]	+	[[Category: Sparrow, C P]]
-	[[Category: Surdo, P Lo.]]	+	[[Category: Surdo, P Lo]]
-	[[Category: Talamo, F.]]	+	[[Category: Talamo, F]]
	[[Category: Cardiovascular disease]]		[[Category: Cardiovascular disease]]
	[[Category: Familial hypercholesterolemia]]		[[Category: Familial hypercholesterolemia]]

OCA at 01:54, 1 October 2014

OCA — Wed, 01 Oct 2014 01:54:21 GMT

←Older revision		Revision as of 01:54, 1 October 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_2w2m\| PDB=2w2m \| SCENE= }}~~	+	==WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR==
-	===WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR===	+	<StructureSection load='2w2m' size='340' side='right' caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>
-	~~{{ABSTRACT_PUBMED_19001363}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2W2M FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [http://www.ebi.ac.uk/pdbsum/2w2m PDBsum]</span></td></tr>
		+	<table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[http://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref> <ref>PMID:2569482</ref> <ref>PMID:3955657</ref> <ref>PMID:8347689</ref> <ref>PMID:2318961</ref> <ref>PMID:1446662</ref> <ref>PMID:1867200</ref> <ref>PMID:8462973</ref> <ref>PMID:8168830</ref> <ref>PMID:2726768</ref> <ref>PMID:1464748</ref> <ref>PMID:7573037</ref> <ref>PMID:7583548</ref> <ref>PMID:7550239</ref> <ref>PMID:7635461</ref> <ref>PMID:7635482</ref> <ref>PMID:7649546</ref> <ref>PMID:7649549</ref> <ref>PMID:8740918</ref> <ref>PMID:8664907</ref> <ref>PMID:9026534</ref> <ref>PMID:9254862</ref> <ref>PMID:9143924</ref> <ref>PMID:9259195</ref> <ref>PMID:9104431</ref> <ref>PMID:9654205</ref> <ref>PMID:9452094</ref> <ref>PMID:9452095</ref> <ref>PMID:9452118</ref> <ref>PMID:10206683</ref> <ref>PMID:10660340</ref> [:]<ref>PMID:9852677</ref> <ref>PMID:9678702</ref> <ref>PMID:10422803</ref> <ref>PMID:10090484</ref> <ref>PMID:10447263</ref> <ref>PMID:10978268</ref> <ref>PMID:10980548</ref> <ref>PMID:10882754</ref> <ref>PMID:11298688</ref> <ref>PMID:17142622</ref> <ref>PMID:19319977</ref> <ref>PMID:22160468</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w2/2w2m_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	PCSK9 regulates low density lipoprotein receptor (LDLR) levels and consequently is a target for the prevention of atherosclerosis and coronary heart disease. Here we studied the interaction, of LDLR EGF(A/AB) repeats with PCSK9. We show that PCSK9 binds the EGF(AB) repeats in a pH-dependent manner. Although the PCSK9 C-terminal domain is not involved in LDLR binding, PCSK9 autocleavage is required. Moreover, we report the x-ray structure of the PCSK9DeltaC-EGF(AB) complex at neutral pH. Compared with the low pH PCSK9-EGF(A) structure, the new structure revealed rearrangement of the EGF(A) His-306 side chain and disruption of the salt bridge with PCSK9 Asp-374, thus suggesting the basis for enhanced interaction at low pH. In addition, the structure of PCSK9DeltaC bound to EGF(AB)(H306Y), a mutant associated with familial hypercholesterolemia (FH), reveals that the Tyr-306 side chain forms a hydrogen bond with PCSK9 Asp-374, thus mimicking His-306 in the low pH conformation. Consistently, Tyr-306 confers increased affinity for PCSK9. Importantly, we found that although the EGF(AB)(H306Y)-PCSK9 interaction is pH-independent, LDLR(H306Y) binds PCSK9 50-fold better at low pH, suggesting that factors other than His-306 contribute to the pH dependence of PCSK9-LDLR binding. Further, we determined the structures of EGF(AB) bound to PCSK9DeltaC containing the FH-associated D374Y and D374H mutations, revealing additional interactions with EGF(A) mediated by Tyr-374/His-374 and providing a rationale for their disease phenotypes. Finally, we report the inhibitory properties of EGF repeats in a cellular assay measuring LDL uptake.

-	~~==Disease==~~	+	Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants.,Bottomley MJ, Cirillo A, Orsatti L, Ruggeri L, Fisher TS, Santoro JC, Cummings RT, Cubbon RM, Lo Surdo P, Calzetta A, Noto A, Baysarowich J, Mattu M, Talamo F, De Francesco R, Sparrow CP, Sitlani A, Carfi A J Biol Chem. 2009 Jan 9;284(2):1313-23. Epub 2008 Nov 10. PMID:19001363<ref>PMID:19001363</ref>
-	~~[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are~~ the ~~cause of hypercholesterolemia autosomal dominant~~ type 3 (~~HCHOLA3~~) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia ~~(FH) [MIM:[http://omim~~.~~org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL~~, ~~and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma)~~, ~~tendons (xanthomas)~~, ~~and coronary arteries~~ (~~atherosclerosis~~).~~<ref>~~PMID:3263645</ref><ref>PMID:2569482</ref><ref>PMID:3955657</ref><ref>PMID:8347689</ref><ref>PMID:2318961</ref><ref>PMID:1446662</ref><ref>PMID:1867200</ref><ref>PMID:8462973</ref><ref>PMID:8168830</ref><ref>PMID:2726768</ref><ref>PMID:1464748</ref><ref>PMID:7573037</ref><ref>PMID:7583548</ref><ref>PMID:7550239</ref><ref>PMID:7635461</ref><ref>PMID:7635482</ref><ref>PMID:7649546</ref><ref>PMID:7649549</ref><ref>PMID:8740918</ref><ref>PMID:8664907</ref><ref>PMID:9026534</ref><ref>PMID:9254862</ref><ref>PMID:9143924</ref><ref>PMID:9259195</ref><ref>PMID:9104431</ref><ref>PMID:9654205</ref><ref>PMID:9452094</ref><ref>PMID:9452095</ref><ref>PMID:9452118</ref><ref>PMID:10206683</ref><ref>PMID:10660340</ref>[:]<ref>PMID:9852677</ref><ref>PMID:9678702</ref><ref>PMID:10422803</ref><ref>PMID:10090484</ref><ref>PMID:10447263</ref><ref>PMID:10978268</ref><ref>PMID:10980548</ref><ref>PMID:10882754</ref><ref>PMID:11298688</ref><ref>PMID:17142622</ref><ref>PMID:19319977</ref><ref>PMID:~~22160468~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~//www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a ~~non-proteolytic mechanism to enhance the degradation~~ of the ~~hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway~~. ~~May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation~~. ~~Can induce ubiquitination~~ of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<~~ref~~>~~PMID:17461796~~</~~ref~~><ref>PMID:18197702</ref><ref>PMID:18660751</ref><ref>PMID:18039658</ref><ref>PMID:22074827</ref><ref>PMID:22580899</ref><ref>PMID:22493497</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.	+	</div>

-	==~~About this Structure~~==	+	==See Also==
-	[[~~2w2m~~]] ~~is a 3 chain structure with sequence from~~ [~~http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from~~ [~~http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA~~].	+	*[[LDL receptor\|LDL receptor]]
-		+	*[[PCSK9\|PCSK9]]
-	==~~Reference~~==	+	== References ==
-	~~<ref group="xtra">PMID:019001363</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Baysarowich, J.]]		[[Category: Baysarowich, J.]]

OCA at 17:15, 24 March 2013

OCA — Sun, 24 Mar 2013 17:15:24 GMT

←Older revision		Revision as of 17:15, 24 March 2013
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-	[[Image:2w2m.png\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_2w2m", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_2w2m\| PDB=2w2m \| SCENE= }}		{{STRUCTURE_2w2m\| PDB=2w2m \| SCENE= }}
-
	===WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR===		===WT PCSK9-DELTAC BOUND TO WT EGF-A OF LDLR===
		+	{{ABSTRACT_PUBMED_19001363}}

		+	==Disease==
		+	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[http://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[http://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref><ref>PMID:2569482</ref><ref>PMID:3955657</ref><ref>PMID:8347689</ref><ref>PMID:2318961</ref><ref>PMID:1446662</ref><ref>PMID:1867200</ref><ref>PMID:8462973</ref><ref>PMID:8168830</ref><ref>PMID:2726768</ref><ref>PMID:1464748</ref><ref>PMID:7573037</ref><ref>PMID:7583548</ref><ref>PMID:7550239</ref><ref>PMID:7635461</ref><ref>PMID:7635482</ref><ref>PMID:7649546</ref><ref>PMID:7649549</ref><ref>PMID:8740918</ref><ref>PMID:8664907</ref><ref>PMID:9026534</ref><ref>PMID:9254862</ref><ref>PMID:9143924</ref><ref>PMID:9259195</ref><ref>PMID:9104431</ref><ref>PMID:9654205</ref><ref>PMID:9452094</ref><ref>PMID:9452095</ref><ref>PMID:9452118</ref><ref>PMID:10206683</ref><ref>PMID:10660340</ref>[:]<ref>PMID:9852677</ref><ref>PMID:9678702</ref><ref>PMID:10422803</ref><ref>PMID:10090484</ref><ref>PMID:10447263</ref><ref>PMID:10978268</ref><ref>PMID:10980548</ref><ref>PMID:10882754</ref><ref>PMID:11298688</ref><ref>PMID:17142622</ref><ref>PMID:19319977</ref><ref>PMID:22160468</ref>

-	~~<!--~~	+	==Function==
-	~~The line below this paragraph~~, ~~{{ABSTRACT_PUBMED_19001363}}~~, ~~adds~~ the ~~Publication Abstract~~ to the ~~page~~	+	[[http://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref><ref>PMID:18197702</ref><ref>PMID:18660751</ref><ref>PMID:18039658</ref><ref>PMID:22074827</ref><ref>PMID:22580899</ref><ref>PMID:22493497</ref> [[http://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
-	~~(as~~ it ~~appears on PubMed at~~ http://www.~~pubmed~~.~~gov)~~, ~~where 19001363 is~~ the ~~PubMed ID number~~.	+
-	-->	+
-	~~{{ABSTRACT_PUBMED_19001363}}~~	+

	==About this Structure==		==About this Structure==
Line 22:		Line 13:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:019001363</ref><references group="xtra"/>	+	<ref group="xtra">PMID:019001363</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Baysarowich, J.]]		[[Category: Baysarowich, J.]]

OCA: Protected "2w2m" [edit=sysop:move=sysop]

OCA — Wed, 24 Aug 2011 05:21:56 GMT

Protected "2w2m" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:21, 24 August 2011

OCA at 05:21, 24 August 2011

OCA — Wed, 24 Aug 2011 05:21:54 GMT

←Older revision		Revision as of 05:21, 24 August 2011
Line 1:		Line 1:
-	{{Seed}}
	[[Image:2w2m.png\|left\|200px]]		[[Image:2w2m.png\|left\|200px]]

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	==About this Structure==		==About this Structure==
-	~~2W2M~~ is a 3 ~~chains~~ structure with ~~sequences~~ from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA].	+	[[2w2m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA].

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~19001363~~</ref><references group="xtra"/>	+	<ref group="xtra">PMID:019001363</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Baysarowich, J.]]		[[Category: Baysarowich, J.]]
Line 44:		Line 43:
	[[Category: Talamo, F.]]		[[Category: Talamo, F.]]
	[[Category: Cardiovascular disease]]		[[Category: Cardiovascular disease]]
-	[[Category: Egf]]
	[[Category: Familial hypercholesterolemia]]		[[Category: Familial hypercholesterolemia]]
-	[[Category: Hydrolase]]	+	[[Category: Hydrolase-receptor complex]]
-	~~[[Category: Hydrolase/~~receptor]]	+
-	~~[[Category: Ldlr~~]]	+
	[[Category: Lipid metabolism]]		[[Category: Lipid metabolism]]
	[[Category: Lipid transport]]		[[Category: Lipid transport]]
-	[[Category: Low-density lipoprotein receptor]]
-	[[Category: Pcsk9]]
-	[[Category: Proprotein convertase]]
-	[[Category: Receptor]]
	[[Category: Serine protease]]		[[Category: Serine protease]]
	[[Category: Steroid metabolism]]		[[Category: Steroid metabolism]]
-
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Sep 22 11:32:49 2010''

←Older revision		Revision as of 11:51, 30 March 2022
Line 3:		Line 3:
	<StructureSection load='2w2m' size='340' side='right'caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='2w2m' size='340' side='right'caption='[[2w2m]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=2W2M FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2w2m]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2W2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2W2M FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1f5y\|1f5y]], [[1hj7\|1hj7]], [[1n7d\|1n7d]], [[2fcw\|2fcw]], [[1i0u\|1i0u]], [[1d2j\|1d2j]], [[1lrx\|1lrx]], [[1hz8\|1hz8]], [[1xfe\|1xfe]], [[1f8z\|1f8z]], [[1ajj\|1ajj]], [[1ldl\|1ldl]], [[1ldr\|1ldr]], [[1ijq\|1ijq]], [[2w2n\|2w2n]], [[2w2p\|2w2p]], [[2w2o\|2w2o]], [[2w2q\|2w2q]]</div></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [~~http~~://pdbe.org/2w2m PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2w2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2w2m OCA], [https://pdbe.org/2w2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2w2m RCSB], [https://www.ebi.ac.uk/pdbsum/2w2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2w2m ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[~~http~~://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[~~http~~://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[~~http~~://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref> <ref>PMID:2569482</ref> <ref>PMID:3955657</ref> <ref>PMID:8347689</ref> <ref>PMID:2318961</ref> <ref>PMID:1446662</ref> <ref>PMID:1867200</ref> <ref>PMID:8462973</ref> <ref>PMID:8168830</ref> <ref>PMID:2726768</ref> <ref>PMID:1464748</ref> <ref>PMID:7573037</ref> <ref>PMID:7583548</ref> <ref>PMID:7550239</ref> <ref>PMID:7635461</ref> <ref>PMID:7635482</ref> <ref>PMID:7649546</ref> <ref>PMID:7649549</ref> <ref>PMID:8740918</ref> <ref>PMID:8664907</ref> <ref>PMID:9026534</ref> <ref>PMID:9254862</ref> <ref>PMID:9143924</ref> <ref>PMID:9259195</ref> <ref>PMID:9104431</ref> <ref>PMID:9654205</ref> <ref>PMID:9452094</ref> <ref>PMID:9452095</ref> <ref>PMID:9452118</ref> <ref>PMID:10206683</ref> <ref>PMID:10660340</ref> [:]<ref>PMID:9852677</ref> <ref>PMID:9678702</ref> <ref>PMID:10422803</ref> <ref>PMID:10090484</ref> <ref>PMID:10447263</ref> <ref>PMID:10978268</ref> <ref>PMID:10980548</ref> <ref>PMID:10882754</ref> <ref>PMID:11298688</ref> <ref>PMID:17142622</ref> <ref>PMID:19319977</ref> <ref>PMID:22160468</ref>	+	[[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 3 (HCHOLA3) [MIM:[https://omim.org/entry/603776 603776]]. A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:12730697</ref> [[https://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Defects in LDLR are the cause of familial hypercholesterolemia (FH) [MIM:[https://omim.org/entry/143890 143890]]; a common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis).<ref>PMID:3263645</ref> <ref>PMID:2569482</ref> <ref>PMID:3955657</ref> <ref>PMID:8347689</ref> <ref>PMID:2318961</ref> <ref>PMID:1446662</ref> <ref>PMID:1867200</ref> <ref>PMID:8462973</ref> <ref>PMID:8168830</ref> <ref>PMID:2726768</ref> <ref>PMID:1464748</ref> <ref>PMID:7573037</ref> <ref>PMID:7583548</ref> <ref>PMID:7550239</ref> <ref>PMID:7635461</ref> <ref>PMID:7635482</ref> <ref>PMID:7649546</ref> <ref>PMID:7649549</ref> <ref>PMID:8740918</ref> <ref>PMID:8664907</ref> <ref>PMID:9026534</ref> <ref>PMID:9254862</ref> <ref>PMID:9143924</ref> <ref>PMID:9259195</ref> <ref>PMID:9104431</ref> <ref>PMID:9654205</ref> <ref>PMID:9452094</ref> <ref>PMID:9452095</ref> <ref>PMID:9452118</ref> <ref>PMID:10206683</ref> <ref>PMID:10660340</ref> [:]<ref>PMID:9852677</ref> <ref>PMID:9678702</ref> <ref>PMID:10422803</ref> <ref>PMID:10090484</ref> <ref>PMID:10447263</ref> <ref>PMID:10978268</ref> <ref>PMID:10980548</ref> <ref>PMID:10882754</ref> <ref>PMID:11298688</ref> <ref>PMID:17142622</ref> <ref>PMID:19319977</ref> <ref>PMID:22160468</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref> [[~~http~~://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.	+	[[https://www.uniprot.org/uniprot/PCSK9_HUMAN PCSK9_HUMAN]] Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.<ref>PMID:17461796</ref> <ref>PMID:18197702</ref> <ref>PMID:18660751</ref> <ref>PMID:18039658</ref> <ref>PMID:22074827</ref> <ref>PMID:22580899</ref> <ref>PMID:22493497</ref> [[https://www.uniprot.org/uniprot/LDLR_HUMAN LDLR_HUMAN]] Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. In case of HIV-1 infection, functions as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells.
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]