View source for 9vjl


==Phosphorylation dependent recognition of RIPK1 by phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1==
<StructureSection load='9vjl' size='340' side='right'caption='[[9vjl]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9vjl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9VJL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9VJL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR,  models</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=9vjl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9vjl OCA], [https://pdbe.org/9vjl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9vjl RCSB], [https://www.ebi.ac.uk/pdbsum/9vjl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9vjl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SHIP1_MOUSE SHIP1_MOUSE] Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Acts as a negative regulator of B-cell antigen receptor signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity. Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the activin/TGF-beta-induced apoptosis through its Smad-dependent expression. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6.<ref>PMID:11136821</ref> <ref>PMID:11222379</ref> <ref>PMID:11359765</ref> <ref>PMID:11896575</ref> <ref>PMID:12161749</ref> <ref>PMID:12370370</ref> <ref>PMID:12447389</ref> <ref>PMID:12882960</ref> <ref>PMID:14993273</ref> <ref>PMID:15166241</ref> <ref>PMID:17142780</ref> <ref>PMID:17173042</ref> <ref>PMID:8654924</ref> <ref>PMID:8805703</ref> <ref>PMID:9244303</ref> <ref>PMID:9620849</ref> <ref>PMID:9736736</ref> <ref>PMID:9763612</ref> <ref>PMID:9857188</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Genome-wide association studies strongly implicate neuroinflammation in late-onset Alzheimer's disease (LOAD). Genetic risk loci for LOAD are enriched for genes expressed in microglia, but the relationship among microglial LOAD risk genes has been unclear. We found that the N-terminal SH2 domain of INPP5D, an important LOAD risk gene, directly interacted with the cell death regulator RIPK1 at p-Y383 to suppress RIPK1 kinase activation. Microglial INPP5D deficiency cell-autonomously promoted RIPK1-mediated transcriptional induction of diverse LOAD risk genes, proinflammatory cytokines, complements, and ROS mediators, as well as proinflammatory signaling mediators such as Toll-like receptors (TLRs), MyD88, Nlrp3, gasdermin D, and Zbp1. RIPK1-regulated microglial transcriptomic signatures were found in microglial subtypes implicated in human Alzheimer's disease (AD) pathogenesis. Furthermore, microglial INPP5D deficiency promoted aging-dependent RIPK1-mediated development of neuronal TDP-43 pathology, neuronal loss, and motor dysfunction in a non-cell-autonomous manner. Our data suggest that INPP5D functions as an intracellular rheostat in regulating RIPK1-mediated neuroinflammation for promoting aging-related neurodegenerative diseases, including LOAD and AD-amyotrophic lateral sclerosis comorbidity.

Repression of RIPK1 kinase by INPP5D inhibits expression of diverse proinflammatory mediators and late-onset Alzheimer's disease risk factors.,Xie X, Liu J, Liang W, Zhang Y, Gong X, Yuan S, Qi C, Huang M, Shi L, Hou M, Zhang M, Liu W, Sun W, Wu Y, Li C, Cao Z, Jing H, Qian L, Liu J, Yuan S, Wang Q, Shen Y, Liu Z, Li Y, Pan H, Zhu B, Shan B, He K, Wang W, Zou C, Li Y, Chou JJ, Yuan J Immunity. 2026 Feb 10;59(2):419-437.e11. doi: 10.1016/j.immuni.2026.01.014. Epub , 2026 Feb 2. PMID:41633359<ref>PMID:41633359</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9vjl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Chou J]]
[[Category: Liu J]]
[[Category: Liu Z]]
[[Category: Sun W]]
[[Category: Xie X]]
[[Category: Xue H]]