OCA at 10:59, 24 December 2020

OCA — Thu, 24 Dec 2020 10:59:01 GMT

←Older revision		Revision as of 10:59, 24 December 2020
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	==Solution NMR Structure of APP TMD==		==Solution NMR Structure of APP TMD==
-	<StructureSection load='6yhf' size='340' side='right'caption='[[6yhf]]' scene=''>	+	<StructureSection load='6yhf' size='340' side='right'caption='[[6yhf]], [[NMR_Ensembles_of_Models \| 20 NMR models]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full ~~crystallographic~~ information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YHF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YHF FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6yhf]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YHF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YHF FirstGlance]. <br>
	</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=6yhf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yhf OCA], [http://pdbe.org/6yhf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yhf RCSB], [http://www.ebi.ac.uk/pdbsum/6yhf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yhf ProSAT]</span></td></tr>		</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=6yhf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yhf OCA], [http://pdbe.org/6yhf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yhf RCSB], [http://www.ebi.ac.uk/pdbsum/6yhf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yhf ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:[http://omim.org/entry/104300 104300]]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.<ref>PMID:8476439</ref> <ref>PMID:15201367</ref> <ref>PMID:1671712</ref> <ref>PMID:1908231</ref> <ref>PMID:1678058</ref> <ref>PMID:1944558</ref> <ref>PMID:1925564</ref> <ref>PMID:1415269</ref> <ref>PMID:1303239</ref> <ref>PMID:1302033</ref> <ref>PMID:1303275</ref> <ref>PMID:8267572</ref> <ref>PMID:8290042</ref> <ref>PMID:8577393</ref> <ref>PMID:9328472</ref> <ref>PMID:9754958</ref> <ref>PMID:10097173</ref> <ref>PMID:10631141</ref> <ref>PMID:10665499</ref> <ref>PMID:10867787</ref> <ref>PMID:11063718</ref> <ref>PMID:11311152</ref> <ref>PMID:11528419</ref> <ref>PMID:12034808</ref> <ref>PMID:15365148</ref> <ref>PMID:15668448</ref> Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:[http://omim.org/entry/605714 605714]]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.<ref>PMID:10821838</ref> <ref>PMID:2111584</ref> <ref>PMID:11409420</ref> <ref>PMID:12654973</ref> <ref>PMID:16178030</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref> N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Cleavage of substrates by gamma-secretase is an inherently slow process where substrate-enzyme affinities cannot be broken down into specific sequence requirements in contrast to soluble proteases. Nevertheless, despite its apparent sequence tolerance single point mutations in amyloid precursor protein can severely affect cleavage efficiencies and change product line preferences. We have determined by NMR spectroscopy the structures of the transmembrane domain of amyloid precursor protein in TFE/water and compared it to that of four mutants: two FAD mutants, V44M and I45T, and the two diglycine hinge mutants, G38L and G38P. In accordance with previous publications, the transmembrane domain is composed of two helical segments connected by the diglycine hinge. Mutations alter kink angles and structural flexibility. Furthermore, to our surprise, we observe different, but specific mutual orientations of N- and C-terminal helical segments in the four mutants compared to the wildtype. We speculate that the observed orientations for G38L, G38P, V44M, and I45T lead to unfavorable interactions with gamma-secretase exosites during substrate movement to the enzyme's active site in presenilin and/or for the accommodation into the substrate-binding cavity of presenilin.
		+
		+	Altered Hinge Conformations in APP Transmembrane Helix Mutants May Affect Enzyme-Substrate Interactions of gamma-Secretase.,Silber M, Hitzenberger M, Zacharias M, Muhle-Goll C ACS Chem Neurosci. 2020 Nov 24. doi: 10.1021/acschemneuro.0c00640. PMID:33232115<ref>PMID:33232115</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6yhf" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Muhle-Goll C]]	+	[[Category: Muhle-Goll, C]]
-	[[Category: Silber M]]	+	[[Category: Silber, M]]
		+	[[Category: App]]
		+	[[Category: Gamma secretase]]
		+	[[Category: Membrane protein]]
		+	[[Category: Transmembrane]]

OCA at 06:37, 9 December 2020

OCA — Wed, 09 Dec 2020 06:37:31 GMT

←Older revision		Revision as of 06:37, 9 December 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6yhf ~~is ON HOLD until Paper Publication~~	+	==Solution NMR Structure of APP TMD==
-		+	<StructureSection load='6yhf' size='340' side='right'caption='[[6yhf]]' scene=''>
-	~~Authors~~: ~~Silber, M~~., ~~Muhle~~-~~Goll~~, C.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YHF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YHF FirstGlance]. <br>
-	~~Description: Solution NMR Structure of APP TMD~~	+	</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=6yhf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yhf OCA], [http://pdbe.org/6yhf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yhf RCSB], [http://www.ebi.ac.uk/pdbsum/6yhf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yhf ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Silber, M~~]]	+	__TOC__
-	[[Category: ~~Muhle-Goll, C~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Muhle-Goll C]]
		+	[[Category: Silber M]]

OCA at 07:23, 22 July 2020

OCA — Wed, 22 Jul 2020 07:23:07 GMT

←Older revision		Revision as of 07:23, 22 July 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6yhf is ON HOLD	+	The entry 6yhf is ON HOLD until Paper Publication

	Authors: Silber, M., Muhle-Goll, C.		Authors: Silber, M., Muhle-Goll, C.

OCA: Protected "6yhf" [edit=sysop:move=sysop]

OCA — Wed, 08 Apr 2020 05:43:30 GMT

Protected "6yhf" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:43, 8 April 2020

OCA: New page: '''Unreleased structure''' The entry 6yhf is ON HOLD Authors: Silber, M., Muhle-Goll, C. Description: Solution NMR Structure of APP TMD Category: Unreleased Structures [[Category: ...

OCA — Wed, 08 Apr 2020 05:43:29 GMT

New page: '''Unreleased structure''' The entry 6yhf is ON HOLD Authors: Silber, M., Muhle-Goll, C. Description: Solution NMR Structure of APP TMD Category: Unreleased Structures [[Category: ...

New page

'''Unreleased structure'''

The entry 6yhf is ON HOLD

Authors: Silber, M., Muhle-Goll, C.

Description: Solution NMR Structure of APP TMD
[[Category: Unreleased Structures]]
[[Category: Silber, M]]
[[Category: Muhle-Goll, C]]

6yhf - Revision history

OCA at 10:59, 24 December 2020

OCA at 06:37, 9 December 2020

OCA at 07:23, 22 July 2020

OCA: Protected "6yhf" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6yhf is ON HOLD Authors: Silber, M., Muhle-Goll, C. Description: Solution NMR Structure of APP TMD Category: Unreleased Structures [[Category: ...