9pd2 | pdb_00009pd2
Crystal structure of PILRA in complex with Fab portion of antagonist antibody
Structural highlights
FunctionPILRA_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 PubMedThe 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
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