|Entry||Database: PDB / ID: 5fwm|
|Title||Atomic cryoEM structure of Hsp90-Cdc37-Cdk4 complex|
|Keywords||CHAPERONE / HSP90 / CDC37 / CDK4 / KINASE / UNFOLDING|
|Function/homology||Cdc37, C-terminal / regulation of lipid biosynthetic process / Cdc37, Hsp90 binding / HSP90-CDC37 chaperone complex / Cdc37 / Cdc37, N-terminal domain / cyclin D2-CDK4 complex / ooplasm / sperm head plasma membrane / negative regulation of transforming growth factor beta activation ...Cdc37, C-terminal / regulation of lipid biosynthetic process / Cdc37, Hsp90 binding / HSP90-CDC37 chaperone complex / Cdc37 / Cdc37, N-terminal domain / cyclin D2-CDK4 complex / ooplasm / sperm head plasma membrane / negative regulation of transforming growth factor beta activation / sulfonylurea receptor binding / Cdc37 N terminal kinase binding / Cdc37 C terminal domain / regulation of lipid catabolic process / Cdc37 Hsp90 binding domain / aryl hydrocarbon receptor complex / dATP binding / CTP binding / cellular response to ionomycin / positive regulation of mitophagy in response to mitochondrial depolarization / cellular response to phorbol 13-acetate 12-myristate / negative regulation of cyclin-dependent protein serine/threonine kinase activity involved in G1/S transition of mitotic cell cycle / Aryl hydrocarbon receptor signalling / histone methyltransferase binding / negative regulation of complement-dependent cytotoxicity / UTP binding / positive regulation of protein localization to cell surface / posttranscriptional regulation of gene expression / cyclin-dependent protein serine/threonine kinase regulator activity / Transcriptional regulation by RUNX2 / protein kinase regulator activity / regulation of insulin receptor signaling pathway / positive regulation of transforming growth factor beta receptor signaling pathway / positive regulation of cell size / supramolecular fiber organization / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / ATP-dependent protein binding / brush border membrane / regulation of interferon-gamma-mediated signaling pathway / lens development in camera-type eye / regulation of cyclin-dependent protein serine/threonine kinase activity / adipose tissue development / The NLRP3 inflammasome / protein targeting / telomerase holoenzyme complex assembly / Uptake and function of diphtheria toxin / regulation of type I interferon-mediated signaling pathway / TPR domain binding / response to cocaine / telomere maintenance via telomerase / positive regulation of phosphoprotein phosphatase activity / inclusion body / chaperone-mediated protein complex assembly / cellular response to interleukin-4 / positive regulation of protein import into nucleus, translocation / DNA polymerase binding / regulation of protein ubiquitination / HSF1 activation / Heat shock hsp90 proteins family signature. / Heat shock protein Hsp90, conserved site / response to testosterone / Sema3A PAK dependent Axon repulsion / PTK6 Regulates Cell Cycle / Heat shock protein Hsp90, N-terminal / HSP90, C-terminal domain / Heat shock protein Hsp90 family / negative regulation of cell cycle arrest / HSF1-dependent transactivation / Hsp90 protein / bicellular tight junction / response to unfolded protein / MHC class II protein complex binding / response to salt stress / positive regulation of G2/M transition of mitotic cell cycle / cyclin-dependent protein kinase holoenzyme complex / Attenuation phase / positive regulation of cell cycle / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Ubiquitin-dependent degradation of Cyclin D1 / cellular response to organic cyclic compound / cyclin binding / heat shock protein binding / positive regulation of protein serine/threonine kinase activity / positive regulation of translation / Hsp90 protein binding / RMTs methylate histone arginines / positive regulation of telomerase activity / Signaling by ERBB2 / nitric-oxide synthase regulator activity / response to lead ion / response to hyperoxia / positive regulation of cell differentiation / HSP90 chaperone cycle for steroid hormone receptors (SHR) / response to toxic substance / xenobiotic metabolic process / regulation of multicellular organism growth / placenta development / Cyclin D associated events in G1 / response to organic substance|
Function and homology information
|Specimen source||Homo sapiens / human /|
|Method||Electron microscopy (8 Å resolution / Particle / Single particle) / Transmission electron microscopy|
|Authors||Verba, K.A. / Wang, R.Y.R. / Arakawa, A. / Liu, Y. / Yokoyama, S. / Agard, D.A.|
|Citation||Journal: Science / Year: 2016|
Title: Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase.
Authors: Kliment A Verba / Ray Yu-Ruei Wang / Akihiko Arakawa / Yanxin Liu / Mikako Shirouzu / Shigeyuki Yokoyama / David A Agard
Abstract: The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" ...The Hsp90 molecular chaperone and its Cdc37 cochaperone help stabilize and activate more than half of the human kinome. However, both the mechanism by which these chaperones assist their "client" kinases and the reason why some kinases are addicted to Hsp90 while closely related family members are independent are unknown. Our structural understanding of these interactions is lacking, as no full-length structures of human Hsp90, Cdc37, or either of these proteins with a kinase have been elucidated. Here we report a 3.9 angstrom cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex. Surprisingly, the two lobes of Cdk4 are completely separated with the β4-β5 sheet unfolded. Cdc37 mimics part of the kinase N lobe, stabilizing an open kinase conformation by wedging itself between the two lobes. Finally, Hsp90 clamps around the unfolded kinase β5 strand and interacts with exposed N- and C-lobe interfaces, protecting the kinase in a trapped unfolded state. On the basis of this structure and an extensive amount of previously collected data, we propose unifying conceptual and mechanistic models of chaperone-kinase interactions.
Copyright: 2016, American Association for the Advancement of Science.
SummaryFull reportAbout validation report
|Date||Deposition: Feb 18, 2016 / Release: Jul 6, 2016|
Downloads & links
A: HEAT SHOCK PROTEIN HSP 90 BETA
B: HEAT SHOCK PROTEIN HSP 90 BETA
E: HSP90 CO-CHAPERONE CDC37
K: CYCLIN-DEPENDENT KINASE 4
Mass: 83645.539 Da / Num. of mol.: 2 / Source: (gene. exp.) Homo sapiens / human / / Plasmid name: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA / References: UniProt:P08238
Mass: 44622.363 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens / human / / Plasmid name: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA / References: UniProt:Q16543
Mass: 34520.629 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens / human / / Plasmid name: PFASTBACHT / Production host: SPODOPTERA FRUGIPERDA / References: UniProt:P11802
Mass: 507.181 Da / Num. of mol.: 2 / Formula: C10H16N5O13P3 / : Adenosine triphosphate / Comment: ATP (energy-carrying molecule) *YM
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: SINGLE PARTICLE|
|Component||Name: COMPLEX OF HUMAN HSP90BETA, HUMAN CDC37 AND HUMAN CDK4|
|Buffer solution||Name: 20MM TRIS-HCL (PH 7.5), 150 MM NACL, 10 MM KCL, 10 MM MGCL2, 20 MM NA2MOO4, 2MM DTT, 0.085MM DDM|
Details: 20MM TRIS-HCL (PH 7.5), 150 MM NACL, 10 MM KCL, 10 MM MGCL2, 20 MM NA2MOO4, 2MM DTT, 0.085MM DDM
|Specimen||Conc.: 0.27 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Details: HOLEY CARBON|
|Vitrification||Instrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Details: LIQUID ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TITAN KRIOS / Date: Nov 25, 2014|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER|
|Electron lens||Mode: BRIGHT FIELD / Nominal magnification: 22500 / Nominal defocus max: 3800 nm / Nominal defocus min: 1400 nm / Cs: 2.7 mm|
|Image recording||Electron dose: 44 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Symmetry||Point symmetry: C1|
|3D reconstruction||Resolution: 8 Å / Number of particles: 61981 / Actual pixel size: 1.315|
Details: THIS MODEL WAS BUILT BASED ON 5FWK WITH CDK4 N-LOBE RIGID BODY FIT INTO THE EM DENSITY. THE MODEL WAS THEN MINIMIZED IN ROSETTA. SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3342. (DEPOSITION ID: 14285).
Symmetry type: POINT
|Atomic model building||Details: METHOD--ROSETTA / Ref protocol: OTHER|
|Least-squares process||Highest resolution: 8 Å|
|Refine hist #LAST||Highest resolution: 8 Å|
|Number of atoms included #LAST||Protein: 14743 / Nucleic acid: 0 / Ligand: 64 / Solvent: 0 / Total: 14807|
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