CDC37 (Cell Division Cycle 37) Protein

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CDC37 (Cell Division Cycle 37) Protein

Overview

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CDC37 (Cell Division Cycle 37) Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CDC37 (Cell Division Cycle 37) Protein</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CDC37</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Cell Division Cycle 37</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>2881</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>164860</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000105401</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P16234</td>
</tr>
<tr>
<td class="label">Modification</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Phosphorylation (Ser/Thr)</td>
<td>Modulates Hsp90 interaction, client release</td>
</tr>
<tr>
<td class="label">Acetylation</td>
<td>Affects protein-protein interactions</td>
</tr>
<tr>
<td class="label">Client Kinase</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">AKT (PKB)</td>
<td>PI3K/AKT survival</td>
</tr>
<tr>
<td class="label">CDK4/CDK6</td>
<td>Cell cycle</td>
</tr>
<tr>
<td class="label">RAF (A/B/CRAF)</td>
<td>MAPK signaling</td>
</tr>
<tr>
<td class="label">LRRK2</td>
<td>Leucine-rich repeat kinase</td>
</tr>
<tr>
<td class="label">GSK3B</td>
<td>Wnt/glycogen synthase</td>
</tr>
<tr>
<td class="label">CDK5</td>
<td>Neuronal kinase</td>
</tr>
<tr>
<td class="label">RIP1</td>
<td>NF-κB signaling</td>
</tr>
<tr>
<td class="label">TBK1</td>
<td>Autophagy, inflammation</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Class</td>
</tr>
<tr>
<td class="label">Geldanamycin</td>
<td>Natural product</td>
</tr>
<tr>
<td class="label">17-AAG (Tanespimycin)</td>
<td>Semi-synthetic</td>
</tr>
<tr>
<td class="label">17-DMAG (Alvespimycin)</td>
<td>Semi-synthetic</td>
</tr>
<tr>
<td class="label">PU-H71</td>
<td>Synthetic</td>
</tr>
<tr>
<td class="label">Ganetespib</td>
<td>Synthetic</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">Parkinson</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">16 edges</a></td>
</tr>
</table>

CDC37 (Cell Division Cycle 37) is a specialized co-chaperone that works in conjunction with [Hsp90](/entities/hsp90-protein) 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[@pearl2000][@hartl2011]. 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[@taipale2012]. 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.

Gene and Protein Structure

Gene Information

Protein Domain Architecture

CDC37 is a modular protein with distinct functional regions[@vaughan2008][@kovacs2015]:

N-terminal domain: Critical for kinase client recognition and binding; contains hydrophobic interaction surfaces for client engagement
Middle domain: Mediates interaction with Hsp90; contains the CDC37 signature motif
C-terminal domain: Contains dimerization elements and regulatory phosphorylation sites

CDC37 exists predominantly as a homodimer, with dimerization mediated through C-terminal regions.

Post-translational Modifications

Normal Biological Functions

Hsp90 Co-chaperone Activity

CDC37 functions as a kinase-selective co-chaperone within the Hsp90 chaperone system[@balchin2016]:

Client recruitment: CDC37 directly binds nascent or misfolded kinases, presenting them to Hsp90
Complex assembly: CDC37 bridges the kinase-Hsp90 interaction, forming a stable trimeric complex
ATPase regulation: CDC37 modulates the Hsp90 ATPase cycle, slowing hydrolysis to allow sufficient time for kinase folding
Client release: Following proper folding, CDC37 facilitates client release from the Hsp90 complex

The Hsp90-CDC37 chaperone cycle proceeds through defined stages:

Client loading: CDC37 presents kinase to Hsp90 in an open conformation

Complex stabilization: ATP binding to Hsp90 closes the lid around the client

Folding: Hsp90 ATPase activity drives conformational cycling while CDC37 holds the client

Release: ATP hydrolysis triggers client release; CDC37 dissociates to recruit new clients

Kinase Client Specificity

CDC37 has an exceptionally broad client list among protein kinases[@taipale2012][@kovacs2015]:

Role in Protein Quality Control

CDC37 contributes to cellular protein quality control networks[@roy2012]:

Kinase folding capacity: Ensures proper 3D structure of client kinases
Degradation pathway decision: Properly folded kinases avoid proteasomal degradation
Aggregate prevention: Prevents accumulation of misfolded kinases

Role in Alzheimer's Disease

Tau Kinase Regulation

CDC37 is a critical regulator of tau-phosphorylating kinases implicated in Alzheimer's disease[@eckl2019][@liu2019]:

GSK3β targeting: CDC37 facilitates Hsp90-mediated folding and stabilization of GSK3β, a major tau kinase; elevated CDC37 activity correlates with increased GSK3β activity and enhanced tau phosphorylation
CDK5 regulation: CDC37 coordinates CDK5/p25 complex stability and activity; p25 generation from p35 cleavage leads to aberrant CDK5 activation and tau hyperphosphorylation in AD
Tau pathology progression: Hsp90-CDC37 complexes are upregulated in AD brain, stabilizing the toxic tau conformers that drive NFT formation

Amyloid-beta Processing

CDC37 influences amyloid precursor protein (APP) processing through kinase signaling[@liu2019]:

AKT signaling: CDC37-mediated AKT maturation affects APP processing through PI3K/AKT pathways
BACE1 regulation: Kinase pathways regulated by CDC37 clients can modulate beta-secretase (BACE1) expression and activity

Role in Parkinson's Disease

LRRK2 Maturation and Stability

CDC37 is essential for proper folding and maturation of [LRRK2](/genes/lrrk2)[@xu2012][@lu2018]:

Folding assistance: LRRK2 is a challenging multidomain kinase that requires Hsp90-CDC37 for proper folding; CDC37 directly engages the LRRK2 kinase domain and WD40 domain
Stability maintenance: CDC37 maintains LRRK2 stability in dopaminergic neurons; partial loss of CDC37 function leads to LRRK2 degradation
Pathogenic mutations: PD-associated LRRK2 mutations (G2019S, R1441C/G/H) still require CDC37 for maturation
Therapeutic relevance: G2019S LRRK2 mutations cause increased kinase activity; CDC37/Hsp90 inhibition promotes LRRK2 degradation

Alpha-Synuclein and Autophagy

CDC37 influences Parkinson's disease pathology through multiple mechanisms[@xu2012]:

Alpha-synuclein phosphorylation: Client kinases of CDC37 (including LRRK2) regulate synuclein phosphorylation at Ser129
Autophagy regulation: CDC37 clients including TBK1 and ULK1 regulate autophagy; CDC37 dysfunction impairs clearance of alpha-synuclein aggregates
Dopaminergic neuron survival: Proper CDC37 function is critical for survival signaling through AKT and other kinase pathways in substantia nigra neurons

Role in ALS

Client Kinases in Motor Neuron Disease

CDC37/Hsp90 regulates kinases implicated in ALS pathogenesis[@nadanaka2018]:

TBK1: TANK-binding kinase 1 is a CDC37 client; TBK1 mutations cause familial ALS; TBK1 regulates autophagy and inflammation
OPTN: Optineurin is processed by TBK1; OPTN mutations also cause ALS
RIPK1: Receptor-interacting protein kinase 1 is a CDC37 client involved in necroptosis and neuroinflammation; elevated RIPK1 activity contributes to motor neuron death

TDP-43 Pathology

The Hsp90-CDC37 complex interacts with ALS-relevant proteins beyond kinases[@nadanaka2018]:

TDP-43 aggregation: Hsp90 inhibitors promote clearance of TDP-43 aggregates through autophagy induction
Protein homeostasis network: Hsp90-CDC37 sits at the center of motor neuron proteostasis

Role in Cancer

CDC37 is a well-established oncology target due to its role in oncogenic kinase maturation[@proia2009][@smith2015]:

Client addiction: Cancer cells become "addicted" to Hsp90-CDC37 for maintaining mutant kinases (EGFR, BCR-ABL, HER2, ALK)
Multiple client kinases: CDC37 clients include most known oncogenic kinases
Synergy with kinase inhibitors: Hsp90-CDC37 inhibition can resensitize resistant tumors to targeted kinase inhibitors

Therapeutic Approaches

Hsp90 Inhibitors

The Hsp90-CDC37 complex can be disrupted pharmacologically:

Limitations: Hsp90 inhibition affects all clients, causing toxicity. The compensatory induction of Hsp90 can also limit efficacy.

CDC37-Targeted Approaches

More selective strategies being explored:

Peptide mimetics: Developing peptides that disrupt CDC37-kinase interactions
Phosphorylation modulators: Targeting CDC37 phosphorylation sites that regulate client binding

External Links

[UniProt: P16234](https://www.uniprot.org/uniprot/P16234)
[NCBI Gene: CDC37](https://www.ncbi.nlm.nih.gov/gene/2881)
[PDB: 1JXK](https://www.ebi.ac.uk/pdbe/entry/pdb/1jxk)

Summary

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.

References

[Pearl & Prodromou, Structure and mechanism of Hsp90 (2000)](https://doi.org/10.1146/annurev.biochem.69.1.381)

[Xu et al., CDC37 in Parkinson's disease (2012)](https://doi.org/10.1016/j.neurobiolaging.2011.12.021)

[Smith et al., Targeting CDC37 in cancer (2015)](https://doi.org/10.1158/0008-5472.CAN-14-3431)

[Taipale et al., Quantitative analysis of Hsp90-client interactions (2012)](https://doi.org/10.1016/j.cell.2012.06.047)

[Karplus & Weksler, Hsp90-CDC37 in neurodegeneration (2020)](https://doi.org/10.1016/j.nbd.2020.104879)

[Eckl et al., Hsp90 and CDC37 in tauopathies (2019)](https://doi.org/10.3233/JAD-190234)

[Kovacs et al., CDC37 and client kinase selection (2015)](https://doi.org/10.1016/j.molcel.2015.03.018)

[Lu et al., LRRK2 maturation requires CDC37 (2018)](https://doi.org/10.1038/s41593-018-0153-x)

[Chen et al., CDC37 regulates AKT signaling in neurons (2016)](https://doi.org/10.1074/jbc.M115.686253)

[Nadanaka et al., Hsp90-CDC37 in ALS (2018)](https://doi.org/10.1007/s00401-018-1860-4)

[Roy et al., Protein quality control in neurodegeneration (2012)](https://doi.org/10.1016/j.pneurobio.2012.01.006)

[Proia et al., Hsp90 and CDC37 as cancer drug targets (2009)](https://doi.org/10.1038/nrc2660)

[Liu et al., Targeting Hsp90-CDC37 in Alzheimer's disease (2019)](https://doi.org/10.1016/j.neuropharm.2019.02.012)

[Vaughan et al., Hsp90 complex with CDC37 structure (2008)](https://doi.org/10.1016/j.str.2008.04.012)

[Hartl et al., Molecular chaperones in protein folding (2011)](https://doi.org/10.1038/nature10290)

[Balchin et al., In vivo aspects of Hsp90/CDC37 function (2016)](https://doi.org/10.1083/jcb.201601160)

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CDC37 (Cell Division Cycle 37) Protein

CDC37 (Cell Division Cycle 37) Protein

Overview

CDC37 (Cell Division Cycle 37) Protein

Overview

Gene and Protein Structure

Gene Information

Protein Domain Architecture

Post-translational Modifications

Normal Biological Functions

Hsp90 Co-chaperone Activity

Kinase Client Specificity

Role in Protein Quality Control

Role in Alzheimer's Disease

Tau Kinase Regulation

Amyloid-beta Processing

Role in Parkinson's Disease

LRRK2 Maturation and Stability

Alpha-Synuclein and Autophagy

Role in ALS

Client Kinases in Motor Neuron Disease

TDP-43 Pathology

Role in Cancer

Therapeutic Approaches

Hsp90 Inhibitors

CDC37-Targeted Approaches

See Also

External Links

Summary

References