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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 / 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
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 19, 2026-
Current statusAug 19, 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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