CDC37 (Cell Division Cycle 37) is a specialized co-chaperone that works in conjunction with Hsp90 to mediate the folding, stabilization, and activation of protein kinases. Originally identified in yeast as an essential cell cycle protein, CDC37 has evolved into a critical regulator of the Hsp90 chaperone system with particular relevance to neurodegenerative diseases[1][2]. Its ability to target specific kinases for Hsp90-mediated maturation makes it a pivotal node in signal transduction networks and a therapeutic target in both cancer and neurodegeneration.
CDC37 acts as a molecular matchmaker, delivering kinase clients to Hsp90 and forming a trimeric chaperone complex that undergoes ATP-dependent cycles of client loading, folding, and release[3]. Unlike general co-chaperones, CDC37 exhibits remarkable specificity for protein kinases as clients, distinguishing it from other Hsp90 co-chaperones that have broader client spectra.
| Property | Value |
|---|---|
| Gene Symbol | CDC37 |
| Full Name | Cell Division Cycle 37 |
| Chromosomal Location | 19p13.3 |
| NCBI Gene ID | 2881 |
| OMIM | 164860 |
| Ensembl ID | ENSG00000105401 |
| UniProt ID | P16234 |
CDC37 is a modular protein with distinct functional regions[4][@kovacs2015]:
CDC37 exists predominantly as a homodimer, with dimerization mediated through C-terminal regions.
| Modification | Effect |
|---|---|
| Phosphorylation (Ser/Thr) | Modulates Hsp90 interaction, client release |
| Acetylation | Affects protein-protein interactions |
CDC37 functions as a kinase-selective co-chaperone within the Hsp90 chaperone system[5]:
The Hsp90-CDC37 chaperone cycle proceeds through defined stages:
CDC37 has an exceptionally broad client list among protein kinases[3:1][@kovacs2015]:
| Client Kinase | Pathway | Disease Relevance |
|---|---|---|
| AKT (PKB) | PI3K/AKT survival | Neuroprotection, cancer |
| CDK4/CDK6 | Cell cycle | Cancer, neuronal development |
| RAF (A/B/CRAF) | MAPK signaling | Cancer, synaptic plasticity |
| LRRK2 | Leucine-rich repeat kinase | Parkinson's disease |
| GSK3B | Wnt/glycogen synthase | Tau phosphorylation, AD |
| CDK5 | Neuronal kinase | Tau pathology, AD |
| RIP1 | NF-κB signaling | Inflammation, cell survival |
| TBK1 | Autophagy, inflammation | ALS, PD |
CDC37 contributes to cellular protein quality control networks[6]:
CDC37 is a critical regulator of tau-phosphorylating kinases implicated in Alzheimer's disease[7][8]:
CDC37 influences amyloid precursor protein (APP) processing through kinase signaling[8:1]:
CDC37 is essential for proper folding and maturation of LRRK2[9][10]:
CDC37 influences Parkinson's disease pathology through multiple mechanisms[9:1]:
CDC37/Hsp90 regulates kinases implicated in ALS pathogenesis[11]:
The Hsp90-CDC37 complex interacts with ALS-relevant proteins beyond kinases[11:1]:
CDC37 is a well-established oncology target due to its role in oncogenic kinase maturation[12][13]:
The Hsp90-CDC37 complex can be disrupted pharmacologically:
| Compound | Class | Status | Notes |
|---|---|---|---|
| Geldanamycin | Natural product | Preclinical | First-in-class Hsp90 inhibitor |
| 17-AAG (Tanespimycin) | Semi-synthetic | Clinical trials | Limited CNS penetration |
| 17-DMAG (Alvespimycin) | Semi-synthetic | Clinical trials | Improved solubility |
| PU-H71 | Synthetic | Clinical trials | CNS-penetrant |
| Ganetespib | Synthetic | Clinical trials | Potent, different scaffold |
Limitations: Hsp90 inhibition affects all clients, causing toxicity. The compensatory induction of Hsp90 can also limit efficacy.
More selective strategies being explored:
CDC37 is a kinase-selective Hsp90 co-chaperone that plays critical roles in protein quality control, signal transduction, and cellular proteostasis. In neurodegeneration, CDC37's client portfolio — LRRK2 in Parkinson's disease, GSK3β and CDK5 in Alzheimer's disease, and TBK1/OPTN in ALS — positions it as a central player in disease pathophysiology. While Hsp90 inhibitors have shown promise in preclinical models, challenges remain regarding CNS penetration, client selectivity, and compensatory chaperone induction.
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Vaughan CK, et al. Hsp90 complex with CDC37: structure and client recognition. Structure. 2008. ↩︎
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