View source for 8grx


==APOE4 receptor in complex with APOE4 NTD==
<StructureSection load='8grx' size='340' side='right'caption='[[8grx]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8grx]] is a 4 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=8GRX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GRX FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#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=8grx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8grx OCA], [https://pdbe.org/8grx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8grx RCSB], [https://www.ebi.ac.uk/pdbsum/8grx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8grx ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/APOE_HUMAN APOE_HUMAN] Defects in APOE are a cause of hyperlipoproteinemia type 3 (HLPP3) [MIM:[https://omim.org/entry/107741 107741]; also known as familial dysbetalipoproteinemia. Individuals with HLPP3 are clinically characterized by xanthomas, yellowish lipid deposits in the palmar crease, or less specific on tendons and on elbows. The disorder rarely manifests before the third decade in men. In women, it is usually expressed only after the menopause. The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of HLPP3 have also been observed in individuals heterozygous for rare APOE variants. The influence of APOE on lipid levels is often suggested to have major implications for the risk of coronary artery disease (CAD). Individuals carrying the common APOE*4 variant are at higher risk of CAD.<ref>PMID:8346443</ref> <ref>PMID:2556398</ref> <ref>PMID:1674745</ref> <ref>PMID:8287539</ref> <ref>PMID:22481068</ref>   Genetic variations in APOE are associated with Alzheimer disease type 2 (AD2) [MIM:[https://omim.org/entry/104310 104310]. It is a late-onset 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. Note=The APOE*4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease. Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE*4 alleles in 42 families with late onset AD. Thus APOE*4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE*4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE*4 participates in pathogenesis is not known.<ref>PMID:8346443</ref>   Defects in APOE are a cause of sea-blue histiocyte disease (SBHD) [MIM:[https://omim.org/entry/269600 269600]; also known as sea-blue histiocytosis. This disorder is characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.<ref>PMID:8346443</ref> <ref>PMID:11095479</ref> <ref>PMID:16094309</ref>   Defects in APOE are a cause of lipoprotein glomerulopathy (LPG) [MIM:[https://omim.org/entry/611771 611771]. LPG is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries. It mainly affects people of Japanese and Chinese origin. The disorder has rarely been described in Caucasians.<ref>PMID:8346443</ref> <ref>PMID:9176854</ref> <ref>PMID:10432380</ref> <ref>PMID:18077821</ref>   Defects in APOE are a cause of familial hypercholesterolemia (FH) [MIM:[https://omim.org/entry/143890 143890]. FH is a condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.<ref>PMID:8346443</ref> <ref>PMID:22949395</ref> 
== Function ==
[https://www.uniprot.org/uniprot/APOE_HUMAN APOE_HUMAN] Mediates the binding, internalization, and catabolism of lipoprotein particles. It can serve as a ligand for the LDL (apo B/E) receptor and for the specific apo-E receptor (chylomicron remnant) of hepatic tissues.
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== Publication Abstract from PubMed ==
The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE isoform dependence remains enigmatic. Here we demonstrate that APOE4, but not APOE2, specifically interacts with the leukocyte immunoglobulin-like receptor B3 (LilrB3). Two discrete immunoglobin-like domains of the LilrB3 extracellular domain (ECD) recognize a positively charged surface patch on the N-terminal domain (NTD) of APOE4. The atomic structure reveals how two APOE4 molecules specifically engage two LilrB3 molecules, bringing their intracellular signaling motifs into close proximity through formation of a hetero-tetrameric complex. Consistent with our biochemical and structural analyses, APOE4, but not APOE2, activates human microglia cells (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. Together, our study identifies LilrB3 as a putative immune cell surface receptor for APOE4, but not APOE2, and may have implications for understanding the biological functions as well as disease relevance of the APOE isoforms.

LilrB3 is a putative cell surface receptor of APOE4.,Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, Shi Y Cell Res. 2023 Feb;33(2):116-130. doi: 10.1038/s41422-022-00759-y. Epub 2023 Jan , 2. PMID:36588123<ref>PMID:36588123</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8grx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Huang G]]
[[Category: Shi Y]]
[[Category: Wang Y]]
[[Category: Zhou J]]