results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.
The results suggested that more complicated mechanisms might be necessary to explain the phosphorylation-activated interaction of Cdc37 with various kinases.
Results found that several disease-linked mutations convert FGFR3 to a stronger client of Hsp90/Cdc37. Enhanced interaction with Cdc37 is underpinned by a weakened N-lobe network. Cdc37 binding to unrelated kinases induces their common extensive remodeling. Kinase remodeling and the kinase/Cdc37 architecture allow recognition by Hsp90.
results of this integrative computational study are compared with a wide range of structural biochemical and cell-based experiments offering a robust network-centric model of allosteric regulation and client kinase recognition by the Hsp90-Cdc37 chaperone machine
During the kinase chaperone cycle Cdc37 phosphorylated at Y298 acts as a platform for docking of non-receptor tyrosine kinases through their regulatory domains to drive the coupled Hsp90 phosphorylation at Y197 and specifically regulate kinase chaperoning.
findings suggested that this mechanism may be exploited by the Hsp90-Cdc37 chaperone to recruit and protect intrinsically dynamic kinase clients from degradation
The results suggest a re-evaluation of the role of Cdc37 in the kinase lifecycle and suggest that such interactions potentially allow kinases to more rapidly respond to key signals while simultaneously protecting unstable kinases from degradation and suppressing unwanted basal activity.
Niclosamide ethanolamine disrupted the interaction between cell division cycle 37 and heat shock protein 90 in hepatocellular carcinoma reducing tumor growth.
Ulk1 promoted the degradation of Hsp90-Cdc37 client kinases resulting in increased cellular sensitivity to Hsp90 inhibitors. Thus our study provides evidence for an anti-proliferative role of Ulk1 in response to Hsp90 inhibition in cancer cells
The authors find that the interaction between sB-Raf and the Hsp90 chaperone system is based on contacts with the M domain of Hsp90 which contributes in forming the ternary complex with Cdc37 as long as the kinase is not stabilized by nucleotide.
Cdc37 performs a quality control of protein kinases including b-raf where induced conformational instability acts as a "flag" for Hsp90 dependence and stable cochaperone association.
The N-terminal tail serves as an intramolecular chaperone ensuring that CDC37 assumes one of two interconvertible states in a manner impacting the interaction of the client binding N-domain and the MC-domains involved in dimerization and HSP90 binding.
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