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- EMDB-66931: Cryo-EM structure of Hsp90(E47A)-FKBP8 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-66931
TitleCryo-EM structure of Hsp90(E47A)-FKBP8 complex
Map data
Sample
  • Complex: Hsp90(E47A)-FKBP8 complex
    • Protein or peptide: Heat shock protein HSP 90-alpha
    • Protein or peptide: Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
KeywordsHsp90 / Fkbp8 / Molecular chaperone / Complex / CHAPERONE
Function / homology
Function and homology information


mitochondrial envelope / regulation of mitophagy / sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly ...mitochondrial envelope / regulation of mitophagy / sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / mitochondrial transport / negative regulation of striated muscle cell apoptotic process / HSP90-CDC37 chaperone complex / AP-3 adaptor complex binding / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / Uptake and function of diphtheria toxin / positive regulation of cell size / dendritic growth cone / TPR domain binding / protein import into mitochondrial matrix / PIWI-interacting RNA (piRNA) biogenesis / response to dietary excess / response to caloric restriction / Assembly and release of respiratory syncytial virus (RSV) virions / negative regulation of protein phosphorylation / non-chaperonin molecular chaperone ATPase / protein localization to mitochondrion / Sema3A PAK dependent Axon repulsion / response to salt stress / regulation of protein ubiquitination / response to unfolded protein / HSF1-dependent transactivation / cardiac muscle cell apoptotic process / regulation of protein-containing complex assembly / Attenuation phase / protein folding chaperone complex / HSF1 activation / enzyme-substrate adaptor activity / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / positive regulation of lamellipodium assembly / RHOBTB2 GTPase cycle / Dengue virus activates/modulates innate and adaptive immune responses / nitric oxide metabolic process / response to isolation stress / protein unfolding / positive regulation of defense response to virus by host / Signaling by ERBB2 / skeletal muscle contraction / eNOS activation / positive regulation of telomere maintenance via telomerase / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / endocytic vesicle lumen / response to cold / DNA polymerase binding / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / cellular response to platelet-derived growth factor stimulus / lysosomal lumen / protein folding chaperone / Recruitment of NuMA to mitotic centrosomes / ESR-mediated signaling / Anchoring of the basal body to the plasma membrane / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / nitric-oxide synthase regulator activity / ATP-dependent protein folding chaperone / response to cocaine / VEGFR2 mediated vascular permeability / brush border membrane / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / endomembrane system / cellular response to virus / positive regulation of protein import into nucleus / neuron migration
Similarity search - Function
: / Tetratricopeptide repeat / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / FKBP-type peptidyl-prolyl cis-trans isomerase ...: / Tetratricopeptide repeat / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / TPR repeat region circular profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
Heat shock protein HSP 90-alpha / Peptidyl-prolyl cis-trans isomerase FKBP8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.09 Å
AuthorsGe M / Li Z / Bai Z / Zhang Y / Zhang Z
Funding support China, 3 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2022ZD0207400 China
National Natural Science Foundation of China (NSFC)32570911 China
National Natural Science Foundation of China (NSFC)32270824 China
CitationJournal: Nat Commun / Year: 2026
Title: FKBP8 connects the Hsp70-Hsp90 chaperone machinery to the folding of membrane proteins.
Authors: Man-Xi Ge / Ming-Zhi Wu / Jia Ji / Zhao-Peng Li / Zhongjian Bai / Jieyan He / Josefa Chuh / Yixiao Zhang / Jing Li / Zai-Rong Zhang /
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 ...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.
History
DepositionNov 4, 2025-
Header (metadata) releaseAug 19, 2026-
Map releaseAug 19, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_66931.png

Downloads & links

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Map

FileDownload / File: emd_66931.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 256 pix.
= 270.08 Å		1.06 Å/pix.
x 256 pix.
= 270.08 Å		1.06 Å/pix.
x 256 pix.
= 270.08 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.055 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-2.176919 - 3.1026316
Average (Standard dev.)0.0020644073 (±0.06762529)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 270.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_66931_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_66931_half_map_2.map
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Sample components

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Entire : Hsp90(E47A)-FKBP8 complex

EntireName: Hsp90(E47A)-FKBP8 complex
Components
  • Complex: Hsp90(E47A)-FKBP8 complex
    • Protein or peptide: Heat shock protein HSP 90-alpha
    • Protein or peptide: Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: Hsp90(E47A)-FKBP8 complex

SupramoleculeName: Hsp90(E47A)-FKBP8 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Heat shock protein HSP 90-alpha

MacromoleculeName: Heat shock protein HSP 90-alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-chaperonin molecular chaperone ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.723688 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRALIS NSSDALDKIR YESLTDPSKL DSGKELHINL IPNKQDRTL TIVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY SAYLVAEKVT VITKHNDDEQ Y AWESSAGG ...String:
MPEETQTQDQ PMEEEEVETF AFQAEIAQLM SLIINTFYSN KEIFLRALIS NSSDALDKIR YESLTDPSKL DSGKELHINL IPNKQDRTL TIVDTGIGMT KADLINNLGT IAKSGTKAFM EALQAGADIS MIGQFGVGFY SAYLVAEKVT VITKHNDDEQ Y AWESSAGG SFTVRTDTGE PMGRGTKVIL HLKEDQTEYL EERRIKEIVK KHSQFIGYPI TLFVEKERDK EVSDDEAEEK ED KEEEKEK EEKESEDKPE IEDVGSDEEE EKKDGDKKKK KKIKEKYIDQ EELNKTKPIW TRNPDDITNE EYGEFYKSLT NDW EDHLAV KHFSVEGQLE FRALLFVPRR APFDLFENRK KKNNIKLYVR RVFIMDNCEE LIPEYLNFIR GVVDSEDLPL NISR EMLQQ SKILKVIRKN LVKKCLELFT ELAEDKENYK KFYEQFSKNI KLGIHEDSQN RKKLSELLRY YTSASGDEMV SLKDY CTRM KENQKHIYYI TGETKDQVAN SAFVERLRKH GLEVIYMIEP IDEYCVQQLK EFEGKTLVSV TKEGLELPED EEEKKK QEE KKTKFENLCK IMKDILEKKV EKVVVSNRLV TSPCCIVTST YGWTANMERI MKAQALRDNS TMGYMAAKKH LEINPDH SI IETLRQKAEA DKNDKSVKDL VILLYETALL SSGFSLEDPQ THANRIYRMI KLGLGIDEDD PTADDTSAAV TEEMPPLE G DDDTSRMEEV D

UniProtKB: Heat shock protein HSP 90-alpha

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Macromolecule #2: Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8

MacromoleculeName: Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidylprolyl isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.808506 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: WLDILGNGLL RKKTLVPGPP GSSRPVKGQV VTVHLQTSLE NGTRVQEEPE LVFTLGDCDV IQALDLSVPL MDVGETAMVT ADSKYCYGP QGSRSPYIPP HAALCLEVTL KTAVDGPDLE MLTGQERVAL ANRKRECGNA HYQRADFVLA ANSYDLAIKA I TSSAKVDM ...String:
WLDILGNGLL RKKTLVPGPP GSSRPVKGQV VTVHLQTSLE NGTRVQEEPE LVFTLGDCDV IQALDLSVPL MDVGETAMVT ADSKYCYGP QGSRSPYIPP HAALCLEVTL KTAVDGPDLE MLTGQERVAL ANRKRECGNA HYQRADFVLA ANSYDLAIKA I TSSAKVDM TFEEEAQLLQ LKVKCLNNLA ASQLKLDHYR AALRSCSLVL EHQPDNIKAL FRKGKVLAQQ GEYSEAIPIL RA ALKLEPS NKTIHAELSK LVKKHAAQRS TETALYRKML GNPS

UniProtKB: Peptidyl-prolyl cis-trans isomerase FKBP8

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 49.41 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.09 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 67866
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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