View source for 6eua


==The fibrinogen-like domain of human Angptl3==
<StructureSection load='6eua' size='340' side='right'caption='[[6eua]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6eua]] 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=6EUA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EUA 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]] 2.095&#8491;</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=6eua FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eua OCA], [https://pdbe.org/6eua PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eua RCSB], [https://www.ebi.ac.uk/pdbsum/6eua PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eua ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ANGL3_HUMAN ANGL3_HUMAN] Familial hypobetalipoproteinemia. The disease is caused by mutations affecting the gene represented in this entry.  May be involved in atherosclerosis. Plasma levels are closely associated with arterial wall thickness.<ref>PMID:17191020</ref>   May be involved in nephrotic syndrome.<ref>PMID:25710887</ref> 
== Function ==
[https://www.uniprot.org/uniprot/ANGL3_HUMAN ANGL3_HUMAN] Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640, PubMed:23661675, PubMed:25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324, PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).[UniProtKB:Q9R182]<ref>PMID:11788823</ref> <ref>PMID:12097324</ref> <ref>PMID:12565906</ref> <ref>PMID:12909640</ref> <ref>PMID:17110602</ref> <ref>PMID:19028676</ref> <ref>PMID:19318355</ref> <ref>PMID:20581395</ref> <ref>PMID:23661675</ref> <ref>PMID:25495645</ref> <ref>PMID:20581395</ref>   ANGPTL3(17-221): In vitro inhibits LPL activity; not effective on GPIHBP1-stabilized LPL.<ref>PMID:19542565</ref>   Involved in angiogenesis. Binds to endothelial cells via integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt signaling pathways and induces cell adhesion and cell migration (PubMed:11877390). Secreted from podocytes, may modulate properties of glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt signaling (PubMed:18535744). May increase the motility of podocytes. May induce actin filament rearrangements in podocytes implicating integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic stem cells (HSC) and is involved in the regulation of HSC activity probably implicating down-regulation of IKZF1/IKAROS (By similarity).[UniProtKB:Q9R182]<ref>PMID:11877390</ref> <ref>PMID:18535744</ref> 
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== Publication Abstract from PubMed ==
Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mutations in these proteins results in up to 34% reduction in coronary artery disease and inhibition of function results in reduced plasma triglyceride levels. Here we report the crystal structures of the fibrinogen-like domains of both proteins. These structures offer new insights into the reported loss of function mutations, the mechanisms of action of the proteins and open up the possibility for the rational design of low molecular weight inhibitors for intervention in coronary artery disease.

Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease.,Biterova E, Esmaeeli M, Alanen HI, Saaranen M, Ruddock LW Sci Rep. 2018 Apr 30;8(1):6752. doi: 10.1038/s41598-018-25237-7. PMID:29713054<ref>PMID:29713054</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6eua" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Alanen HI]]
[[Category: Biterova EI]]
[[Category: Esmaeeli ME]]
[[Category: Ruddock LW]]
[[Category: Saaranen M]]