6qly

From Proteopedia

(Difference between revisions)

Current revision

IDOL FERM domain

Structural highlights

6qly is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.5Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MYLIP_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Hepatic abundance of the Low-Density lipoprotein receptor (LDLR) is a critical determinant of circulating plasma LDL-cholesterol levels and hence development of coronary artery disease. The sterol-responsive E3 ubiquitin ligase Inducible Degrader of the LDLR (IDOL) specifically promotes ubiquitination and subsequent lysosomal degradation of the LDLR and thus controls cellular LDL uptake. IDOL contains an extended N-terminal FERM (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) domain, responsible for substrate recognition and plasma-membrane association, and a second C-terminal RING domain, responsible for the E3 ligase activity and homo-dimerization. As IDOL is a putative lipid-lowering drug-target we investigated the molecular details of its substrate recognition. We produced and isolated full-length IDOL protein, which displayed high auto-ubiquitination activity. However, in vitro ubiquitination of its substrate, the intracellular tail of the LDLR, was low. To investigate the structural basis for this we determined crystal structures of the extended FERM domain of IDOL and multiple conformations of its F3ab subdomain. These reveal the archetypal F1-F2-F3 tri-lobed FERM domain structure but show that the F3c subdomain orientation obscures the target binding site. To substantiate this finding, we analyzed the full length FERM domain and a series of truncated FERM constructs by small angle X-ray scattering (SAXS). The scattering data support a compact and globular core FERM domain with a more flexible and extended C-terminal region. This flexibility may explain the low activity in vitro and suggests that IDOL may require activation for recognition of the LDLR.

Structural analysis of the LDL receptor-interacting FERM domain in the E3 ubiquitin ligase IDOL reveals an obscured substrate binding site.,Martinelli L, Adamopoulos A, Johansson P, Wan PT, Gunnarsson J, Guo H, Boyd H, Zelcer N, Sixma TK J Biol Chem. 2020 Jul 29. pii: RA120.014349. doi: 10.1074/jbc.RA120.014349. PMID:32727844^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Olsson PA, Korhonen L, Mercer EA, Lindholm D. MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth. J Biol Chem. 1999 Dec 17;274(51):36288-92. PMID:10593918
↑ Bornhauser BC, Johansson C, Lindholm D. Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR. FEBS Lett. 2003 Oct 9;553(1-2):195-9. PMID:14550572
↑ Bornhauser BC, Olsson PA, Lindholm D. MSAP is a novel MIR-interacting protein that enhances neurite outgrowth and increases myosin regulatory light chain. J Biol Chem. 2003 Sep 12;278(37):35412-20. Epub 2003 Jun 24. PMID:12826659 doi:10.1074/jbc.M306271200
↑ Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 2009 Jul 3;325(5936):100-4. doi: 10.1126/science.1168974. Epub 2009 Jun , 11. PMID:19520913 doi:10.1126/science.1168974
↑ Hong C, Duit S, Jalonen P, Out R, Scheer L, Sorrentino V, Boyadjian R, Rodenburg KW, Foley E, Korhonen L, Lindholm D, Nimpf J, van Berkel TJ, Tontonoz P, Zelcer N. The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. J Biol Chem. 2010 Jun 25;285(26):19720-6. doi: 10.1074/jbc.M110.123729. Epub 2010, Apr 28. PMID:20427281 doi:10.1074/jbc.M110.123729
↑ Calkin AC, Goult BT, Zhang L, Fairall L, Hong C, Schwabe JW, Tontonoz P. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20107-12. doi:, 10.1073/pnas.1111589108. Epub 2011 Nov 22. PMID:22109552 doi:10.1073/pnas.1111589108
↑ Martinelli L, Adamopoulos A, Johansson P, Wan PT, Gunnarsson J, Guo H, Boyd H, Zelcer N, Sixma TK. Structural analysis of the LDL receptor-interacting FERM domain in the E3 ubiquitin ligase IDOL reveals an obscured substrate binding site. J Biol Chem. 2020 Jul 29. pii: RA120.014349. doi: 10.1074/jbc.RA120.014349. PMID:32727844 doi:http://dx.doi.org/10.1074/jbc.RA120.014349

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6qly"

Categories: Homo sapiens | Large Structures | Martinelli L | Sixma TK

@@ Line 3: / Line 3: @@
 <StructureSection load='6qly' size='340' side='right'caption='[[6qly]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6qly]] is a 1 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=6QLY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6QLY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6qly]] is a 1 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=6QLY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QLY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.5&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MYLIP, BZF1, IDOL, BM-023, PP5242 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RING-type_E3_ubiquitin_transferase RING-type E3 ubiquitin transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.27 2.3.2.27] </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=6qly FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qly OCA], [https://pdbe.org/6qly PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qly RCSB], [https://www.ebi.ac.uk/pdbsum/6qly PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qly 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=6qly FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qly OCA], [http://pdbe.org/6qly PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qly RCSB], [http://www.ebi.ac.uk/pdbsum/6qly PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qly ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/MYLIP_HUMAN MYLIP_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.<ref>PMID:10593918</ref> <ref>PMID:14550572</ref> <ref>PMID:12826659</ref> <ref>PMID:19520913</ref> <ref>PMID:20427281</ref> <ref>PMID:22109552</ref>
+[https://www.uniprot.org/uniprot/MYLIP_HUMAN MYLIP_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.<ref>PMID:10593918</ref> <ref>PMID:14550572</ref> <ref>PMID:12826659</ref> <ref>PMID:19520913</ref> <ref>PMID:20427281</ref> <ref>PMID:22109552</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: RING-type E3 ubiquitin transferase]]
+[[Category: Martinelli L]]
-[[Category: Martinelli, L]]
+[[Category: Sixma TK]]
-[[Category: Sixma, T K]]
-[[Category: Ferm domain]]
-[[Category: Ldlr degradation]]
-[[Category: Ligase]]
-[[Category: Ubiquitin e3 ligase cholesterol metabolism]]

6qly

From Proteopedia

Current revision

IDOL FERM domain

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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Proteopedia Page Contributors and Editors (what is this?)

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