HSP90-CDC37 chaperone complex

Definition

Target type: cellularcomponent

A protein kinase chaperone complex required for the proper folding, maturation and stabilization of target proteins (mostly signaling protein kinases, some steroid hormone receptors), usually during or immediately after completion of translation. The highly conserved, phosphorylated CDC37-Ser13 (vertebrates) or cdc37-Ser14 (yeast) is essential for complex assembly and target protein binding. CDC37-Ser13 (Ser14) is phosphorylated by Casein kinase II (CK2), which in turn is a target of CDC37 creating a positive feedback loop. Complex binding also prevents rapid ubiquitin-dependent proteosomal degradation of target proteins. [GOC:bhm, GOC:pad, GOC:PARL, PMID:21855797, PMID:22939624]

The HSP90-CDC37 chaperone complex is a molecular machine that plays a crucial role in the folding, maturation, and stabilization of a diverse array of client proteins, particularly kinases. This complex is found in the cytoplasm of eukaryotic cells and is composed of two major components:

* **Heat Shock Protein 90 (HSP90):** A highly conserved molecular chaperone that acts as a scaffold for the complex. It possesses two domains: an N-terminal domain that binds ATP and a C-terminal domain that interacts with cochaperones and client proteins. HSP90's primary function is to provide a stable and protected environment for client proteins to undergo conformational changes during their maturation.

* **CDC37 (Cell Division Cycle 37):** A specific cochaperone that binds to HSP90 and is essential for the complex's ability to interact with kinases. CDC37 acts as a "kinase adaptor" by recognizing and binding to a specific motif within kinases, facilitating their recruitment to the HSP90-CDC37 complex. This interaction ensures the proper folding and activation of the kinase clients.

The HSP90-CDC37 complex operates in a dynamic and iterative manner, employing a cycle of ATP binding and hydrolysis to facilitate client protein maturation. This cycle involves multiple steps:

1. **Client Protein Binding:** The complex initially binds to unfolded or misfolded client proteins, particularly kinases. This binding is often facilitated by other cochaperones like Hop (Hsp70/Hsp90 organizing protein) and p23.

2. **ATP Binding and Conformational Changes:** Upon ATP binding to the N-terminal domain of HSP90, the complex undergoes a conformational change, creating a more enclosed environment for the client protein. This change promotes proper folding and maturation of the client.

3. **ATP Hydrolysis and Release:** The hydrolysis of ATP by HSP90 leads to a further conformational shift in the complex, ultimately releasing the properly folded and activated client protein.

The HSP90-CDC37 chaperone complex is crucial for the function of a wide range of cellular processes, including signal transduction, cell cycle regulation, and development. Its involvement in the folding and activation of kinases is particularly critical, as these enzymes play central roles in numerous signaling pathways. Disruptions in the function of the HSP90-CDC37 complex have been implicated in various diseases, including cancer, neurodegeneration, and inflammation. These findings highlight the importance of this complex in maintaining cellular homeostasis and underscore its potential as a therapeutic target.'
"

Proteins (1)

Compounds (43)