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- PDB-9xj8: Cryo-EM structure of Hsp90(E47A)-FKBP8 complex -

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Basic information

Entry
Database: PDB / ID: 9xj8
TitleCryo-EM structure of Hsp90(E47A)-FKBP8 complex
Components
  • Heat shock protein HSP 90-alpha
  • Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8
KeywordsCHAPERONE / Hsp90 / Fkbp8 / Molecular chaperone / Complex
Function / homology
Function and homology information


mitochondrial envelope / protein localization to mitochondrion / regulation of mitophagy / sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly ...mitochondrial envelope / protein localization to mitochondrion / regulation of mitophagy / sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / mitochondrial transport / dATP 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 / protein import into mitochondrial matrix / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / negative regulation of protein phosphorylation / non-chaperonin molecular chaperone ATPase / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / response to salt stress / protein folding chaperone complex / HSF1-dependent transactivation / cardiac muscle cell apoptotic process / response to unfolded protein / regulation of protein-containing complex assembly / Attenuation phase / HSF1 activation / enzyme-substrate adaptor activity / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / telomere maintenance via telomerase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / Dengue virus activates/modulates innate and adaptive immune responses / nitric oxide metabolic process / response to cold / protein unfolding / positive regulation of defense response to virus by host / skeletal muscle contraction / Signaling by ERBB2 / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of telomere maintenance via telomerase / endocytic vesicle lumen / DNA polymerase binding / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / Recruitment of mitotic centrosome proteins and complexes / endomembrane system / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / protein folding chaperone / 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 / protein tyrosine kinase binding / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / nitric-oxide synthase regulator activity / ATP-dependent protein folding chaperone / VEGFR2 mediated vascular permeability / peptidylprolyl isomerase / brush border membrane / peptidyl-prolyl cis-trans isomerase activity / response to cocaine / cellular response to virus / positive regulation of protein import into nucleus / myelin sheath / neuron migration / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / protein refolding / Regulation of actin dynamics for phagocytic cup formation / DDX58/IFIH1-mediated induction of interferon-alpha/beta
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
ADENOSINE-5'-TRIPHOSPHATE / Heat shock protein HSP 90-alpha / Peptidyl-prolyl cis-trans isomerase FKBP8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.09 Å
AuthorsGe, M. / Li, Z. / Bai, Z. / Zhang, Y. / Zhang, Z.
Funding support China, 3items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 19, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
B: Heat shock protein HSP 90-alpha
E: Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)201,2705
Polymers200,2563
Non-polymers1,0142
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Heat shock protein HSP 90-alpha / Heat shock 86 kDa / HSP 86 / HSP86 / Heat shock protein family C member 1 / Lipopolysaccharide- ...Heat shock 86 kDa / HSP 86 / HSP86 / Heat shock protein family C member 1 / Lipopolysaccharide-associated protein 2 / LAP-2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 84723.688 Da / Num. of mol.: 2 / Mutation: E47A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Homo sapiens (human)
References: UniProt: P07900, non-chaperonin molecular chaperone ATPase
#2: Protein Isoform 2 of Peptidyl-prolyl cis-trans isomerase FKBP8 / PPIase FKBP8 / 38 kDa FK506-binding protein / 38 kDa FKBP / FKBP-38 / hFKBP38 / FK506-binding ...PPIase FKBP8 / 38 kDa FK506-binding protein / 38 kDa FKBP / FKBP-38 / hFKBP38 / FK506-binding protein 8 / FKBP-8 / FKBPR38 / Rotamase


Mass: 30808.506 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP8, FKBP38 / Production host: Homo sapiens (human) / References: UniProt: Q14318, peptidylprolyl isomerase
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Hsp90(E47A)-FKBP8 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 49.41 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameCategory
1RELIONparticle selection
2EPUimage acquisition
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 67866 / Symmetry type: POINT

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