9pd2

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of PILRA in complex with Fab portion of antagonist antibody

Structural highlights

9pd2 is a 3 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 2.579Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PILRA_HUMAN Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRA is thought to act as a cellular signaling inhibitory receptor by recruiting cytoplasmic phosphatases like PTPN6/SHP-1 and PTPN11/SHP-2 via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Receptor for PIANP.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.

Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.,Weerakkody TN, Sabelstrom H, Andrews SV, Chadarevian JP, Chin MY, Tatarakis D, Propson NE, Kim DJ, Theolis R, Parico GCG, Misker H, Kung JE, Bandyopadhyay A, Robles Colmenares Y, Jackson TN, Qerqez AN, Balasundar S, Davis SS, Ha C, Ghosh R, Ravi R, Rana A, Germain K, Tao A, Xiong K, Braun D, Raju K, Huang KC, Zhan L, Guo JL, Safari Yazd H, Sarrafha L, Capocchi JK, Hasselmann J, Chadarevian AL, Tu C, Mansour K, Eskandari-Sedighi G, Tesi N, van der Lee S, Hulsman M, Oshegov G, Pijnenburg Y, Calvert M, Holstege H, Suh JH, Di Paolo G, Davtyan H, Lewcock JW, Blurton-Jones M, Monroe KM Sci Transl Med. 2025 Dec 3;17(827):eadw7428. doi: 10.1126/scitranslmed.adw7428. , Epub 2025 Dec 3. PMID:41337541^[4]

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

References

↑ Fournier N, Chalus L, Durand I, Garcia E, Pin JJ, Churakova T, Patel S, Zlot C, Gorman D, Zurawski S, Abrams J, Bates EE, Garrone P. FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells. J Immunol. 2000 Aug 1;165(3):1197-209. PMID:10903717
↑ Satoh T, Arii J, Suenaga T, Wang J, Kogure A, Uehori J, Arase N, Shiratori I, Tanaka S, Kawaguchi Y, Spear PG, Lanier LL, Arase H. PILRalpha is a herpes simplex virus-1 entry coreceptor that associates with glycoprotein B. Cell. 2008 Mar 21;132(6):935-44. PMID:18358807 doi:http://dx.doi.org/S0092-8674(08)00205-5
↑ Kogure A, Shiratori I, Wang J, Lanier LL, Arase H. PANP is a novel O-glycosylated PILRalpha ligand expressed in neural tissues. Biochem Biophys Res Commun. 2011 Feb 18;405(3):428-33. doi:, 10.1016/j.bbrc.2011.01.047. Epub 2011 Jan 15. PMID:21241660 doi:http://dx.doi.org/10.1016/j.bbrc.2011.01.047
↑ Weerakkody TN, Sabelström H, Andrews SV, Chadarevian JP, Chin MY, Tatarakis D, Propson NE, Kim DJ, Theolis R, Parico GCG, Misker H, Kung JE, Bandyopadhyay A, Robles Colmenares Y, Jackson TN, Qerqez AN, Balasundar S, Davis SS, Ha C, Ghosh R, Ravi R, Rana A, Germain K, Tao A, Xiong K, Braun D, Raju K, Huang KC, Zhan L, Guo JL, Safari Yazd H, Sarrafha L, Capocchi JK, Hasselmann J, Chadarevian AL, Tu C, Mansour K, Eskandari-Sedighi G, Tesi N, van der Lee S, Hulsman M, Oshegov G, Pijnenburg Y, Calvert M, Holstege H, Suh JH, Di Paolo G, Davtyan H, Lewcock JW, Blurton-Jones M, Monroe KM. Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease. Sci Transl Med. 2025 Dec 3;17(827):eadw7428. PMID:41337541 doi:10.1126/scitranslmed.adw7428

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9pd2"

Categories: Homo sapiens | Large Structures | Kung JE

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9pd2 is ON HOLD
+==Crystal structure of PILRA in complex with Fab portion of antagonist antibody==
+<StructureSection load='9pd2' size='340' side='right'caption='[[9pd2]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9pd2]] 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=9PD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9PD2 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]] 2.579&#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=9pd2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9pd2 OCA], [https://pdbe.org/9pd2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9pd2 RCSB], [https://www.ebi.ac.uk/pdbsum/9pd2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9pd2 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PILRA_HUMAN PILRA_HUMAN] Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRA is thought to act as a cellular signaling inhibitory receptor by recruiting cytoplasmic phosphatases like PTPN6/SHP-1 and PTPN11/SHP-2 via their SH2 domains that block signal transduction through dephosphorylation of signaling molecules. Receptor for PIANP.<ref>PMID:10903717</ref> <ref>PMID:18358807</ref> <ref>PMID:21241660</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
-Authors:
+Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease.,Weerakkody TN, Sabelstrom H, Andrews SV, Chadarevian JP, Chin MY, Tatarakis D, Propson NE, Kim DJ, Theolis R, Parico GCG, Misker H, Kung JE, Bandyopadhyay A, Robles Colmenares Y, Jackson TN, Qerqez AN, Balasundar S, Davis SS, Ha C, Ghosh R, Ravi R, Rana A, Germain K, Tao A, Xiong K, Braun D, Raju K, Huang KC, Zhan L, Guo JL, Safari Yazd H, Sarrafha L, Capocchi JK, Hasselmann J, Chadarevian AL, Tu C, Mansour K, Eskandari-Sedighi G, Tesi N, van der Lee S, Hulsman M, Oshegov G, Pijnenburg Y, Calvert M, Holstege H, Suh JH, Di Paolo G, Davtyan H, Lewcock JW, Blurton-Jones M, Monroe KM Sci Transl Med. 2025 Dec 3;17(827):eadw7428. doi: 10.1126/scitranslmed.adw7428. , Epub 2025 Dec 3. PMID:41337541<ref>PMID:41337541</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 9pd2" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Kung JE]]

9pd2

From Proteopedia

Current revision

Crystal structure of PILRA in complex with Fab portion of antagonist antibody

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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