Hsp90·Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites.
Protein kinases are the most prominent group of heat shock protein 90 (Hsp90) clients and are recruited to the molecular chaperone by the kinase-specific cochaperone cell division cycle 37 (Cdc37). The interaction between Hsp90 and nematode Cdc37 is mediated by binding of the Hsp90 middle domain to an N-terminal region of Caenorhabditis elegans Cdc37 (CeCdc37). Here we map the binding site by NMR spectroscopy and define amino acids relevant for the interaction between CeCdc37 and the middle domain of Hsp90. Apart from these distinct Cdc37/Hsp90 interfaces, binding of the B-Raf protein kinase to the cochaperone is conserved between mammals and nematodes. In both cases, the C-terminal part of Cdc37 is relevant for kinase binding, whereas the N-terminal domain displaces the nucleotide from the kinase. This interaction leads to a cooperative formation of the ternary complex of Cdc37 and kinase with Hsp90. For the mitogen-activated protein kinase extracellular signal-regulated kinase 2 (Erk2), we observe that certain features of the interaction with Cdc37·Hsp90 are conserved, but the contribution of Cdc37 domains varies slightly, implying that different kinases may utilize distinct variations of this binding mode to interact with the Hsp90 chaperone machinery.
From the Center for Integrated Protein Science München at Department of Chemistry, Technische Universität München, 85748 Garching, Germany and.
Julia M
JM
Eckl
From the Center for Integrated Protein Science München at Department of Chemistry, Technische Universität München, 85748 Garching, Germany and.
Matthias J
MJ
Scherr
From the Center for Integrated Protein Science München at Department of Chemistry, Technische Universität München, 85748 Garching, Germany and Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Lee
L
Freiburger
From the Center for Integrated Protein Science München at Department of Chemistry, Technische Universität München, 85748 Garching, Germany and.
Marina A
MA
Daake
From the Center for Integrated Protein Science München at Department of Chemistry, Technische Universität München, 85748 Garching, Germany and Institute of Structural Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Michael
M
Sattler
From the Center for Integrated Protein Science München at Department of Chemistry, Technische Universität München, 85748 Garching, Germany and klaus.richter@richterlab.de.
Klaus
K
Richter
D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018833:Chaperonins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
C515008:CDC-37 protein, C elegans; C498362:CDC37 protein, human; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C510188:DAF-21 protein, C elegans; D018841:HSP90 Heat-Shock Proteins; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D018833:Chaperonins
Cdc37; Raf-kinase; chaperone; cochaperone; heat shock protein 90 (Hsp90); protein complex; protein kinase; protein-protein interaction