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- EMDB-23051: Focused map of the Hsp90-Hsp70-Hop-GR client-loading complex: Hsp... -

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Basic information

Entry
Database: EMDB / ID: EMD-23051
TitleFocused map of the Hsp90-Hsp70-Hop-GR client-loading complex: Hsp90-CTDs:Hop-DP2:GR-Helix1
Map dataRaw (unsharpened) map from Relion's refine3d.
Sample
  • Complex: Hsp90-Hsp70-Hop-GR complex
Function / homology
Function and homology information


Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / dynein axonemal particle / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / microglia differentiation / mammary gland duct morphogenesis ...Regulation of NPAS4 gene transcription / regulation of glucocorticoid biosynthetic process / nuclear glucocorticoid receptor activity / dynein axonemal particle / steroid hormone binding / PTK6 Expression / neuroinflammatory response / glucocorticoid metabolic process / microglia differentiation / mammary gland duct morphogenesis / maternal behavior / astrocyte differentiation / cellular response to interleukin-7 / protein folding chaperone complex / cellular response to glucocorticoid stimulus / RND1 GTPase cycle / motor behavior / sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / regulation of gluconeogenesis / adrenal gland development / protein insertion into mitochondrial outer membrane / cellular response to steroid hormone stimulus / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / mitochondrial transport / 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 / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / HSF1-dependent transactivation / positive regulation of cell size / response to unfolded protein / telomere maintenance via telomerase / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / estrogen response element binding / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / eNOS activation / axonal growth cone / positive regulation of lamellipodium assembly / DNA polymerase binding / nuclear receptor-mediated steroid hormone signaling pathway / core promoter sequence-specific DNA binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / : / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of defense response to virus by host / cellular response to transforming growth factor beta stimulus / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Recruitment of NuMA to mitotic centrosomes / response to salt stress / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / TBP-class protein binding / activation of innate immune response / nitric-oxide synthase regulator activity / steroid binding / positive regulation of interferon-beta production / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / lysosomal lumen / ESR-mediated signaling / cellular response to dexamethasone stimulus
Similarity search - Function
STI1/HOP, DP domain / STI1/HOP, DP domain / Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Glucocorticoid receptor / Glucocorticoid receptor / Heat shock chaperonin-binding / Heat shock chaperonin-binding motif. / TPR repeat / Tetratricopeptide repeat ...STI1/HOP, DP domain / STI1/HOP, DP domain / Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Glucocorticoid receptor / Glucocorticoid receptor / Heat shock chaperonin-binding / Heat shock chaperonin-binding motif. / TPR repeat / Tetratricopeptide repeat / 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 / TPR repeat region circular profile. / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Zinc finger, C4 type (two domains) / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type / Tetratricopeptide-like helical domain superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
Glucocorticoid receptor / Heat shock protein HSP 90-alpha / Stress-induced-phosphoprotein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsWang RY / Agard DA
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2022
Title: Structure of Hsp90-Hsp70-Hop-GR reveals the Hsp90 client-loading mechanism.
Authors: Ray Yu-Ruei Wang / Chari M Noddings / Elaine Kirschke / Alexander G Myasnikov / Jill L Johnson / David A Agard /
Abstract: Maintaining a healthy proteome is fundamental for the survival of all organisms. Integral to this are Hsp90 and Hsp70, molecular chaperones that together facilitate the folding, remodelling and ...Maintaining a healthy proteome is fundamental for the survival of all organisms. Integral to this are Hsp90 and Hsp70, molecular chaperones that together facilitate the folding, remodelling and maturation of the many 'client proteins' of Hsp90. The glucocorticoid receptor (GR) is a model client protein that is strictly dependent on Hsp90 and Hsp70 for activity. Chaperoning GR involves a cycle of inactivation by Hsp70; formation of an inactive GR-Hsp90-Hsp70-Hop 'loading' complex; conversion to an active GR-Hsp90-p23 'maturation' complex; and subsequent GR release. However, to our knowledge, a molecular understanding of this intricate chaperone cycle is lacking for any client protein. Here we report the cryo-electron microscopy structure of the GR-loading complex, in which Hsp70 loads GR onto Hsp90, uncovering the molecular basis of direct coordination by Hsp90 and Hsp70. The structure reveals two Hsp70 proteins, one of which delivers GR and the other scaffolds the Hop cochaperone. Hop interacts with all components of the complex, including GR, and poises Hsp90 for subsequent ATP hydrolysis. GR is partially unfolded and recognized through an extended binding pocket composed of Hsp90, Hsp70 and Hop, revealing the mechanism of GR loading and inactivation. Together with the GR-maturation complex structure, we present a complete molecular mechanism of chaperone-dependent client remodelling, and establish general principles of client recognition, inhibition, transfer and activation.
History
DepositionNov 30, 2020-
Header (metadata) releaseDec 8, 2021-
Map releaseDec 8, 2021-
UpdateFeb 2, 2022-
Current statusFeb 2, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23051.png

Downloads & links

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Map

FileDownload / File: emd_23051.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRaw (unsharpened) map from Relion's refine3d.
Voxel sizeX=Y=Z: 1.059 Å
Density
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.036287714 - 0.080865026
Average (Standard dev.)-0.00014063272 (±0.0019734863)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 338.88 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0591.0591.059
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z338.880338.880338.880
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0360.081-0.000

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Supplemental data

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Sample components

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Entire : Hsp90-Hsp70-Hop-GR complex

EntireName: Hsp90-Hsp70-Hop-GR complex
Components
  • Complex: Hsp90-Hsp70-Hop-GR complex

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Supramolecule #1: Hsp90-Hsp70-Hop-GR complex

SupramoleculeName: Hsp90-Hsp70-Hop-GR complex / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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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: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Details: The Hsp90 semi-open conformation from the Hsp90:Hop cryo-EM structure from Southworth & Agard (2011).
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 43626
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 3.0)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 80

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