Sandbox Reserved 1472
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== Mechanics & Energetics == | == Mechanics & Energetics == | ||
| - | Hsp90 and the co-chaperone Cdc37 are responsible for about 60% of kinases to achieve an active state<ref name="verba>PMID:27339980</ref>. One of the questions that researchers have had is why some kinases are clients of Hsp90 and Cdc37 and not others. There is evidence Cdc37 works by recognizing conformational instability of kinase clients and changing their folding landscapes as it binds to the client and recruits it to Hsp90<ref>PMID:29267381</ref>. In this way Cdc37 would be selecting kinase clients for Hsp90, where less thermodynamically stable clients would be delivered to Hsp90 and more stable clients would not. The open and closed conformations of Hsp90 are driven by the binding and release of | + | Hsp90 and the co-chaperone Cdc37 are responsible for about 60% of kinases to achieve an active state<ref name="verba">PMID:27339980</ref>. One of the questions that researchers have had is why some kinases are clients of Hsp90 and Cdc37 and not others. There is evidence Cdc37 works by recognizing conformational instability of kinase clients and changing their folding landscapes as it binds to the client and recruits it to Hsp90<ref>PMID:29267381</ref>. In this way Cdc37 would be selecting kinase clients for Hsp90, where less thermodynamically stable clients would be delivered to Hsp90 and more stable clients would not. The open and closed conformations of Hsp90 are driven by the binding and release of |
adenosine triphosphate (ATP) in the N-terminal domain (NTD), where the closed state has ATP bound and the open state does not. Before Hsp90 will interact with Cdc37 and Cdk4 evidence points to the NTD of Cd37 being the region that recognizes both client and non-client kinases. When the NTD of Cdc37 was removed it was found to fail in interacting with bRaf, another known kinase client of the Hsp90-Cd37 system<ref>PMID:27105117</ref>. | adenosine triphosphate (ATP) in the N-terminal domain (NTD), where the closed state has ATP bound and the open state does not. Before Hsp90 will interact with Cdc37 and Cdk4 evidence points to the NTD of Cd37 being the region that recognizes both client and non-client kinases. When the NTD of Cdc37 was removed it was found to fail in interacting with bRaf, another known kinase client of the Hsp90-Cd37 system<ref>PMID:27105117</ref>. | ||
Revision as of 01:16, 5 December 2018
| This Sandbox is Reserved from November 5 2018 through January 1, 2019 for use in the course "CHEM 4923: Senior Project taught by Christina R. Bourne at the University of Oklahoma, Norman, USA. This reservation includes Sandbox Reserved 1471 through Sandbox Reserved 1478. |
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Hsp90-Cdc37-Cdk4 Complex
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Function
The Hsp90-Cdc37-Cdk4 complex is made up of the Heat Shock Protein 90 chaperone molecule, Cell Division Cycle 37 co-chaperone molecule, and the Cyclin-dependent 4 Kinase client molecule. Hsp90 is a 90-kDa protein that acts as a molecular chaperone for a variety of client proteins the majority of which are involved in signal transduction. It belongs to a group of proteins called heat shock proteins. Heat shock proteins are named for the response that organisms exhibit due to stresses at a cellular level such as elevated temperatures beyond the normal existing environment cells usually cope with. A major feature of this response is an alteration of an organism’s gene expression through increased heat shock protein production[1]. Cdc37 is one the the main co-chaperones of Hsp90, it recruits kinase proteins for late folding and activation by binding to the kinase and delivering it to Hsp90. Cdk4 is a part of a kinase complex that is needed for cell cycle G1 phase progression. For the activation of Cdk4 there must be proper folding, binding of the regulator cyclin D, ATP binding, a positioning of the active site near the ATP binding site and phosphorylation of the amino acid residue T172. Hsp90 and the co-chaperone Cdc37 plays a crucial role in the late folding process of Cdk4 needed for its activation of which is critical for cell development[2].
Mechanics & Energetics
Hsp90 and the co-chaperone Cdc37 are responsible for about 60% of kinases to achieve an active state[3]. One of the questions that researchers have had is why some kinases are clients of Hsp90 and Cdc37 and not others. There is evidence Cdc37 works by recognizing conformational instability of kinase clients and changing their folding landscapes as it binds to the client and recruits it to Hsp90[4]. In this way Cdc37 would be selecting kinase clients for Hsp90, where less thermodynamically stable clients would be delivered to Hsp90 and more stable clients would not. The open and closed conformations of Hsp90 are driven by the binding and release of adenosine triphosphate (ATP) in the N-terminal domain (NTD), where the closed state has ATP bound and the open state does not. Before Hsp90 will interact with Cdc37 and Cdk4 evidence points to the NTD of Cd37 being the region that recognizes both client and non-client kinases. When the NTD of Cdc37 was removed it was found to fail in interacting with bRaf, another known kinase client of the Hsp90-Cd37 system[5].
Relevance
Structural highlights
In the cryo-electron microscopy structure of the Hsp90-Cdc37-Cdk4 complex the β4-β5 sheet is unfolded which separates the two lobes of Cdk4, Cdc37 wedges itself between these lobes, and Hsp90 clamps around the β5 sheet of Cdk4[3]
