Biochemical and structural studies of the interaction of Cdc37 with Hsp90.
The heat shock protein Hsp90 plays a key, but poorly understood role in the folding, assembly and activation of a large number of signal transduction molecules, in particular kinases and steroid hormone receptors. In carrying out these functions Hsp90 hydrolyses ATP as it cycles between ADP- and ATP-bound forms, and this ATPase activity is regulated by the transient association with a variety of co-chaperones. Cdc37 is one such co-chaperone protein that also has a role in client protein recognition, in that it is required for Hsp90-dependent folding and activation of a particular group of protein kinases. These include the cyclin-dependent kinases (Cdk) 4/6 and Cdk9, Raf-1, Akt and many others. Here, the biochemical details of the interaction of human Hsp90 beta and Cdc37 have been characterised. Small angle X-ray scattering (SAXS) was then used to study the solution structure of Hsp90 and its complexes with Cdc37. The results suggest a model for the interaction of Cdc37 with Hsp90, whereby a Cdc37 dimer binds the two N-terminal domain/linker regions in an Hsp90 dimer, fixing them in a single conformation that is presumably suitable for client protein recognition.
Zhang
Wei
W
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
Hirshberg
Miriam
M
McLaughlin
Stephen H
SH
Lazar
Greg A
GA
Grossmann
J Günter
JG
Nielsen
Peter R
PR
Sobott
Frank
F
Robinson
Carol V
CV
Jackson
Sophie E
SE
Laue
Ernest D
ED
D000042:Absorption; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002138:Calibration; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D018833:Chaperonins; D002850:Chromatography, Gel; D019281:Dimerization; D029721:Drosophila Proteins / Q000737:chemistry / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000235:genetics; D014644:Genetic Variation; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D016018:Least-Squares Analysis; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry* / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D010455:Peptides / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D012996:Solutions / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D020860:Subtilisin / Q000494:pharmacology; D014461:Ultracentrifugation; D014961:X-Ray Diffraction
C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D010455:Peptides; D011993:Recombinant Fusion Proteins; D012996:Solutions; D000255:Adenosine Triphosphate; D020860:Subtilisin; D000251:Adenosine Triphosphatases; D018833:Chaperonins