p50cdc37 Is a Nonexclusive Hsp90 Cohort Which Participates Intimately in Hsp90-Mediated Folding of Immature Kinase Molecules

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Abstract
Hsp90 and p50cdc37 provide a poorly understood biochemical function essential to certain protein kinases, and recent models describe p50cdc37 as an exclusive hsp90 cohort which links hsp90 machinery to client kinases. We describe here the recovery of p50cdc37 in immunoadsorptions directed against the hsp90 cohorts FKBP52, cyp40, p60HOP, hsp70, and p23. Additionally, monoclonal antibodies against FKBP52 coadsorb maturation intermediates of the hsp90-dependent kinases p56lck and HRI, and the presence of these maturation intermediates significantly increases the representation of p50cdc37 and hsp90 on FKPB52 machinery. Although the native heterocomplex between hsp90 and p50cdc37 is salt-labile, their dynamic interactions with kinase substrates produce kinase−chaperone heterocomplexes which are highly salt-resistant. The hsp90 inhibitor geldanamycin does not directly disrupt the native association of hsp90 with p50cdc37 per se, but does result in the formation of salt-labile hsp90−kinase heterocomplexes which lack the p50cdc37 cohort. We conclude that p50cdc37 does not simply serve as a passive structural bridge between hsp90 and its kinase substrates; instead, p50cdc37 is a nonexclusive hsp90 cohort which responds to hsp90's nucleotide-regulated conformational switching during the generation of high-affinity interactions within the hsp90−kinase−p50cdc37 heterocomplex.