View source for 6qly


==IDOL FERM domain==
<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 [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='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='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='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>
</table>
== Function ==
[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 ==
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<ref>PMID:32727844</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6qly" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Martinelli L]]
[[Category: Sixma TK]]