{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE333nnn/GSE333678/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Homo sapiens"],"gds_type":["Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE333678"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"FKBP8 connects the Hsp70-Hsp90 chaperone machinery to the folding of membrane proteins","description":"The folding of membrane protein cytoplasmic domains on the endoplasmic reticulum (ER) surface, and their coordination with transmembrane and exoplasmic regions, remains poorly understood. Through a genome-wide CRISPR-Cas9 screen, we identified the ER-anchored FK506 binding protein 8 (FKBP8) as a chaperone essential for membrane protein folding and assembly. Using ABC transporters as model substrates, we show that FKBP8 cooperates with Hsp70-Hsp90 machinery to remodel nascent or misfolded cytosolic domains into their native conformations. Cryo-EM analysis reveals that FKBP8 employs a conserved hydrophobic ϕ94ϕ96ϕ97/ϕ158ϕ162 cluster to help form a large client-binding cavity within the FKBP8–Hsp90 complex that captures folding intermediates. FKBP8 deficiency, disruption of this cluster, or disease-associated mutations within FKBP8 abolish substrate maturation, leading to ER retention and degradation. Reconstitution with purified components demonstrates that FKBP8 and Hsp40-Hsp70-HOP-Hsp90 constitute a minimal machinery capable of restoring the native structure of a misfolded ABC transporter. These findings uncover a dedicated folding module at the ER-cytosol interface that bridges cytosolic chaperones with membrane protein quality control, suggesting a broad role for FKBP8 in safeguarding the biogenesis of complex membrane proteins.","dates":{"publication":"2026/08/08"},"accession":"GSE333678","cross_references":{"GSM":["GSM9770763","GSM9770762"],"GPL":["24676"],"GSE":["333678"],"taxon":["Homo sapiens"],"PMID":["[42321214]"]}}