9XJ8

Cryo-EM structure of Hsp90(E47A)-FKBP8 complex

Summary for 9XJ8

• Entry DOI: 10.2210/pdb9xj8/pdb
• EMDB information: 66931
• Descriptor: Heat shock protein HSP 90-alpha, Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8, ADENOSINE-5'-TRIPHOSPHATE (3 entities in total)
• Functional Keywords: hsp90, fkbp8, molecular chaperone, complex, chaperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 201270.24

Authors

Ge, M.,Li, Z.,Bai, Z.,Zhang, Y.,Zhang, Z. (deposition date: 2025-11-04, release date: 2026-08-19)

Primary citation

Ge, M.X.,Wu, M.Z.,Ji, J.,Li, Z.P.,Bai, Z.,He, J.,Chuh, J.,Zhang, Y.,Li, J.,Zhang, Z.R.
FKBP8 connects the Hsp70-Hsp90 chaperone machinery to the folding of membrane proteins.
Nat Commun, 2026

PubMed Abstract: 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 ϕϕϕ/ϕϕ 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.

PubMed: 42321214
DOI: 10.1038/s41467-026-74519-6

Experimental method

ELECTRON MICROSCOPY (4.09 Å)