CDC37 encodes an essential cytosolic Hsp90 co-chaperone that specializes the Hsp90 system for protein kinase clients. Cdc37 binds protein kinases and Hsp90, promotes Hsp90-kinase complex formation, protects nascent kinase chains from rapid degradation, and supports post-translational kinase maturation. Its client effects explain downstream roles in Cdc28/Cak1-dependent cell-cycle progression, MAP kinase signaling, osmotic and cell wall stress responses, and spindle pole body duplication, but the core function is kinase-specific chaperone/adaptor activity rather than those downstream pathways themselves.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: The phylogenetic cytoplasm annotation is consistent with experimental localization and with Cdc37 acting in cytosolic Hsp90-kinase complexes.
Reason: Cdc37 is experimentally detected in the cytoplasm and its core Hsp90 co-chaperone activity is carried out in the cytosolic chaperone machinery.
Supporting Evidence:
PMID:14562095
Global analysis of protein localization in budding yeast.
file:yeast/CDC37/CDC37-deep-research-falcon.md
Cdc37's functional locale is best described as the cytosolic chaperone machinery, where it forms transient Cdc37-kinase and Hsp90-Cdc37-kinase complexes.
|
|
GO:0006457
protein folding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Cdc37 is a kinase-directed Hsp90 co-chaperone required for productive folding and maturation of protein kinases.
Reason: Although Cdc37 is not a general foldase for all proteins, the annotation accurately captures its core role in protein kinase folding/maturation in the Hsp90 pathway.
Supporting Evidence:
PMID:17242065
Cdc37 functions at distinct steps in kinase biogenesis that involves protecting nascent chains from rapid degradation followed by its folding function in association with Hsp90.
file:yeast/CDC37/CDC37-deep-research-falcon.md
Cdc37 selectively recognizes kinase clients and promotes their stabilization and productive engagement with Hsp90 to achieve folding/maturation and functional activation.
|
|
GO:0031072
heat shock protein binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: The annotation reflects the well-established physical and functional interaction between Cdc37 and Hsp90.
Reason: Hsp90 binding is central to Cdc37 function as a kinase-targeting adaptor and is supported by biochemical and genetic evidence for Hsp90-Cdc37-kinase complexes.
Supporting Evidence:
PMID:9242486
The identification of Cdc37 as the 50-kD protein in several Hsp90-kinase complexes, together with other data, led to the recent suggestion that Cdc37 is a kinase-targeting "subunit" of Hsp90.
PMID:17220467
The interaction of Hsp90, Slt2p, and Hog1p with Cdc37p depends on the phosphorylation status of Cdc37p.
|
|
GO:0050821
protein stabilization
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Protein stabilization is a core biological process for Cdc37, specifically stabilization of protein kinase clients.
Reason: Multiple studies show that Cdc37 maintains kinase abundance and protects newly synthesized kinases from degradation.
Supporting Evidence:
PMID:17242065
showed that 51 had decreased abundance compared with levels in the wild-type strain.
file:yeast/CDC37/CDC37-deep-research-falcon.md
In a panel of 65 kinases, 51 showed decreased abundance in a cdc37 mutant, supporting a broad role in kinase homeostasis.
|
|
GO:0051082
unfolded protein binding
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: Cdc37 does bind non-native kinase clients, but the broad "unfolded protein binding" term obscures the kinase-specific co-chaperone mechanism.
Reason: Replace the generic binding term with protein-folding chaperone activity; kinase client binding is already captured by the accepted GO:0019901 annotation.
Proposed replacements:
protein folding chaperone
Supporting Evidence:
PMID:17242065
Cdc37 protects nascent kinase chains from rapid degradation shortly after synthesis.
|
|
GO:0051087
protein-folding chaperone binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: This term captures Cdc37 binding to the Hsp90 chaperone machinery.
Reason: Protein-folding chaperone binding is a core molecular interaction for Cdc37, which couples kinase clients to Hsp90.
Supporting Evidence:
PMID:9242486
the very similar chaperone activities of the two proteins, uncovered through in vitro analysis, diverge in vivo in specific signal transduction pathways.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: UniProtKB subcellular-location mapping to cytoplasm is correct.
Reason: The automated cytoplasm annotation agrees with the experimental localization and the cytosolic Hsp90 co-chaperone function.
Supporting Evidence:
UniProt:P06101
SUBCELLULAR LOCATION: Cytoplasm.
|
|
GO:0019901
protein kinase binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: InterPro-derived protein kinase binding is highly specific and captures the key client-recognition activity of Cdc37.
Reason: Cdc37 is a kinase-targeting co-chaperone, and protein kinase binding is the most informative currently annotated molecular function for its client specificity.
Supporting Evidence:
UniProt:P06101
Co-chaperone that binds to numerous kinases and promotes their interaction with the Hsp90 complex, resulting in their stabilization.
file:yeast/CDC37/CDC37-deep-research-falcon.md
Cdc37 selectively recognizes kinase clients and promotes their stabilization and productive engagement with Hsp90.
|
|
GO:0051301
cell division
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: Cell division is a true consequence of Cdc37 activity through Cdc28/Cak1 and spindle-pole-body kinase clients, but it is not the molecular core function of Cdc37.
Reason: Retain as a supported downstream biological process while keeping the core function focused on kinase-specific chaperoning and stabilization.
Supporting Evidence:
PMID:7753858
Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins.
file:yeast/CDC37/CDC37-deep-research-falcon.md
CDC37 is essential for G1/Start progression and for activation of the major cyclin-dependent kinase Cdc28.
|
|
GO:0005515
protein binding
|
IPI
PMID:15766533 Navigating the chaperone network: an integrative map of phys... |
MARK AS OVER ANNOTATED |
Summary: This high-throughput interaction annotation is real evidence of physical interactions but the term is too generic for Cdc37.
Reason: Protein binding does not distinguish Cdc37's specific Hsp90/kinase co-chaperone role; specific kinase and chaperone binding annotations are more informative.
|
|
GO:0005515
protein binding
|
IPI
PMID:15879519 A two-hybrid screen of the yeast proteome for Hsp90 interact... |
MARK AS OVER ANNOTATED |
Summary: The interaction evidence supports Hsp90 pathway biology but the generic protein binding term is uninformative.
Reason: Use specific Hsp90/chaperone and kinase-client terms rather than generic protein binding for Cdc37.
|
|
GO:0005515
protein binding
|
IPI
PMID:16554755 Global landscape of protein complexes in the yeast Saccharom... |
MARK AS OVER ANNOTATED |
Summary: Large-scale complex data document interactions but do not by themselves define a specific molecular function.
Reason: Generic protein binding is over-annotated for a co-chaperone whose specific binding modes are captured by protein kinase binding and protein-folding chaperone binding.
|
|
GO:0005515
protein binding
|
IPI
PMID:19536198 An atlas of chaperone-protein interactions in Saccharomyces ... |
MARK AS OVER ANNOTATED |
Summary: The chaperone-protein interaction atlas supports Cdc37 involvement in the chaperone network, but the GO term is too broad.
Reason: The annotation should not be treated as core because more specific chaperone and kinase-client binding terms describe the function.
|
|
GO:0005737
cytoplasm
|
HDA
PMID:14562095 Global analysis of protein localization in budding yeast. |
ACCEPT |
Summary: High-throughput localization to cytoplasm agrees with the known site of Cdc37-Hsp90 kinase-chaperone action.
Reason: Cytoplasm is a supported core cellular component for Cdc37.
|
|
GO:0043410
positive regulation of MAPK cascade
|
IMP
PMID:17220467 Cdc37p is required for stress-induced high-osmolarity glycer... |
KEEP AS NON CORE |
Summary: Cdc37 positively affects HOG and PKC MAPK pathway output by stabilizing and interacting with Hog1 and Slt2.
Reason: This is well-supported pathway-level biology but is downstream of the core kinase-chaperone function.
Supporting Evidence:
PMID:17220467
levels of the MAPKs Hog1p and Slt2p (Mpk1p) in cells are reduced in a cdc37-S14A mutant
|
|
GO:0071474
cellular hyperosmotic response
|
IMP
PMID:17220467 Cdc37p is required for stress-induced high-osmolarity glycer... |
KEEP AS NON CORE |
Summary: The hyperosmotic-response phenotype is supported by cdc37-S14A effects on Hog1/Hsp90/Cdc37 interactions.
Reason: Retain as a valid stress-response annotation, but do not elevate it above the kinase-specific chaperone role.
Supporting Evidence:
PMID:17220467
Mutation of the phosphorylation site Ser14 in Cdc37p renders cells sensitive to osmotic stress.
|
|
GO:0071852
fungal-type cell wall organization or biogenesis
|
IMP
PMID:17220467 Cdc37p is required for stress-induced high-osmolarity glycer... |
KEEP AS NON CORE |
Summary: Cdc37 affects cell wall stress responses through the Slt2/PKC MAPK pathway.
Reason: This is a supported downstream pathway consequence of kinase chaperoning, not the core molecular role.
Supporting Evidence:
PMID:17220467
during cell wall stress, the interaction of Slt2p with Cdc37p and Hsp90 is crucial for Slt2p-dependent downstream responses
|
|
GO:0038066
p38MAPK cascade
|
IPI
PMID:17220467 Cdc37p is required for stress-induced high-osmolarity glycer... |
KEEP AS NON CORE |
Summary: In yeast this annotation reflects Hog1 MAPK interaction and pathway support by Cdc37.
Reason: The physical interaction is relevant but represents a client/pathway context rather than the core function of Cdc37.
Supporting Evidence:
PMID:17220467
Hog1p and Slt2p both interact in a complex with Cdc37p in vivo.
|
|
GO:0071474
cellular hyperosmotic response
|
IPI
PMID:17220467 Cdc37p is required for stress-induced high-osmolarity glycer... |
KEEP AS NON CORE |
Summary: Interaction with Hog1 supports Cdc37 participation in osmotic stress signaling.
Reason: The annotation is valid as pathway context but should remain non-core relative to the kinase-chaperone activity.
Supporting Evidence:
PMID:17220467
the osmosensitive phenotype of the cdc37-S14A mutant is due to the loss of the interaction between Cdc37p, Hog1p, and Hsp90.
|
|
GO:0030474
spindle pole body duplication
|
IMP
PMID:9060463 The yeast CDC37 gene interacts with MPS1 and is required for... |
KEEP AS NON CORE |
Summary: Cdc37 is required for proper spindle pole body duplication, likely through kinase-client biology involving Mps1.
Reason: Retain as a supported cell-cycle phenotype, but classify as non-core because it is downstream of Cdc37's kinase-chaperone role.
Supporting Evidence:
PMID:9060463
The yeast CDC37 gene interacts with MPS1 and is required for proper execution of spindle pole body duplication.
|
|
GO:0050821
protein stabilization
|
IMP
PMID:17242065 Cdc37 has distinct roles in protein kinase quality control t... |
ACCEPT |
Summary: This annotation directly captures the experimentally demonstrated role of Cdc37 in kinase abundance and nascent-chain quality control.
Reason: Protein stabilization of kinase clients is central to Cdc37 function.
Supporting Evidence:
PMID:17242065
Results from our pulse-labeling studies showed that Cdc37 protects nascent kinase chains from rapid degradation shortly after synthesis.
|
|
GO:0051082
unfolded protein binding
|
IDA
PMID:9242486 Cdc37 is a molecular chaperone with specific functions in si... |
MODIFY |
Summary: The experiment supports molecular chaperone activity, but the GO term is too generic for Cdc37's kinase-directed function.
Reason: Replace generic unfolded protein binding with protein folding chaperone, while leaving protein kinase binding to the existing accepted GO:0019901 annotation.
Proposed replacements:
protein folding chaperone
Supporting Evidence:
PMID:9242486
In vitro, Cdc37 maintains denatured beta-galactosidase in an activation-competent state without reactivating it and stabilizes mature, but unstable, casein kinase II.
|
|
GO:0051726
regulation of cell cycle
|
IMP
PMID:7753858 Cdc37 is required for association of the protein kinase Cdc2... |
KEEP AS NON CORE |
Summary: Cdc37 regulates cell-cycle progression through effects on the cyclin- dependent kinase Cdc28.
Reason: Cell-cycle regulation is an important downstream consequence of kinase chaperoning but should not be treated as the primary molecular function.
Supporting Evidence:
PMID:7753858
Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins.
|
Q: Which yeast kinase clients require Cdc37 primarily for nascent-chain stabilization versus later Hsp90-dependent maturation?
Q: Are there yeast stress conditions that shift Cdc37 client specificity beyond the kinases already surveyed by abundance and interaction assays?
Experiment: Pulse-SILAC or equivalent time-resolved proteomics in phosphosite and temperature-sensitive cdc37 mutants, paired with kinase activity assays, to separate defects in kinase synthesis, stability, and maturation.
Hypothesis: Distinct kinase subclasses show different dependence on Cdc37 for nascent-chain stabilization versus post-translational maturation.
Type: quantitative proteomics
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The provided UniProt record describes Cdc37, an Hsp90 co-chaperone (also called the kinase-targeting subunit/p50) from Saccharomyces cerevisiae S288c, encoded by CDC37 (systematic locus YDR168W). The retrieved yeast primary literature consistently describes S. cerevisiae Cdc37 as an essential factor for protein-kinase stability/maturation that functions with Hsp90 and is regulated by CK2-dependent phosphorylation at conserved N-terminal serines (Ser14/Ser17 in yeast), matching the functional and regulatory features in the UniProt description. This corpus did not contain an explicit statement linking the accession number P06101 to CDC37/YDR168W, so accession-level mapping is not independently cross-validated here; the functional identity and organism match are strong and yeast-specific. (farrell2000cdc37promotesthe pages 1-2, mandal2007cdc37hasdistinct pages 1-3, miyata2004ck2controlsmultiple pages 1-2, millson2014cdc37engagesin pages 1-2)
Cdc37 is a protein-kinase–directed co-chaperone/adaptor in the cytosolic Hsp90 system. Rather than catalyzing a chemical reaction, Cdc37 selectively recognizes kinase clients and promotes their stabilization and productive engagement with Hsp90 to achieve folding/maturation and functional activation. (mandal2007cdc37hasdistinct pages 1-3, miyata2004ck2controlsmultiple pages 1-2)
A widely used mechanistic model assigns separable roles to Cdc37 domains:
- N-terminal domain/region: primary kinase-binding module; binds determinants in the kinase catalytic domain (often mapped to the N-lobe of kinases). (mandal2007cdc37hasdistinct pages 1-3, verba2017howhsp90and pages 4-6)
- Middle domain: major Hsp90-binding interface (binding Hsp90 N-terminal and/or middle domain depending on cycle state), helping recruit kinases into the Hsp90 cycle. (verba2017howhsp90and pages 4-6)
- C-terminal region: contributes to client interactions in some species/contexts; in yeast it can be partly dispensable in some experimental settings discussed in review literature. (verba2017howhsp90and pages 4-6)
A structural feature highlighted in expert review is that a conserved Cdc37 motif can mimic part of the kinase αC–β4 loop, stabilizing a partially unfolded kinase conformation that can be further remodeled by Hsp90, providing a physical rationale for kinase selectivity. (verba2017howhsp90and pages 4-6)
Supporting visual evidence: Verba & Agard (2017) provide a schematic of Cdc37 domain architecture and a model of the Hsp90–Cdc37–kinase cycle. (verba2017howhsp90and media 39c974c8, verba2017howhsp90and media fe609c0f)
A consistent mechanistic theme is that Cdc37 helps load kinases onto Hsp90 and can inhibit/arrest Hsp90 ATPase-coupled conformational progression during client loading (e.g., by blocking lid closure/NTD dimerization), thereby stabilizing intermediate complexes until the client is ready for productive folding steps. (guimaraes2022developmentofa pages 20-25, verba2017howhsp90and pages 4-6)
In budding yeast, CDC37 is essential for G1/Start progression and for activation of the major cyclin-dependent kinase Cdc28 (Cdk1). In the temperature-sensitive cdc37-1 mutant, Cdc28 shows multiple defects including reduced total protein and reduced activity; importantly, Cdc28 protein levels were reported as ~3–5-fold lower than wild type in cdc37-1. (farrell2000cdc37promotesthe pages 1-2)
Cdc37 also supports the stability/activity of the CDK-activating kinase Cak1. The same primary study reported that Cak1 levels and activity are reduced in cdc37-1, supporting the view that Cdc37 is a general kinase biogenesis factor with particularly strong effects on key cell-cycle kinases. (farrell2000cdc37promotesthe pages 1-2, farrell2000cdc37promotesthe pages 5-6)
A large-scale analysis (sampling 65 yeast protein kinases, ~50% of the kinome) found that 51 kinases had decreased abundance in a cdc37 mutant background, supporting a broad role for Cdc37 in kinase quality control and kinome stability. The same work proposed a two-step model: (i) protection of newly synthesized kinases from rapid degradation and (ii) post-translational maturation with Hsp90. (mandal2007cdc37hasdistinct pages 1-3)
Independent yeast genetic/interaction work further supports broad kinase dependence on Cdc37 phosphorylation state: the nonphosphorylatable cdc37(S14A) allele is temperature sensitive and was reported to destabilize ~70% of the kinome (as summarized in yeast-focused work on Cak1–Cdc37 association). (millson2014cdc37engagesin pages 1-2)
A central regulatory input is casein kinase 2 (CK2)-dependent phosphorylation of Cdc37 at a conserved N-terminal serine (Ser13 in mammals; Ser14/Ser17 in yeast numbering discussed in yeast literature). CK2-dependent phosphorylation is described as essential for optimal engagement of Cdc37 with a wide set of protein kinases and for productive Hsp90–kinase complex formation, while certain Cdc37 mutants can retain Hsp90 binding but lose effective kinase handling. (miyata2004ck2controlsmultiple pages 1-2, millson2014cdc37engagesin pages 1-2)
This establishes CDC37 as a node by which CK2 can coordinately influence the stability and activity of many kinases through a chaperone-mediated mechanism. (miyata2004ck2controlsmultiple pages 1-2)
Beyond core cell-cycle kinases, CDC37 connects to signaling. In a study of osmoadaptation, the cdc37-34 mutant showed osmosensitivity not explained by canonical HOG signaling defects; instead, the filamentous growth MAPK module (Ste11/Ste7/Kss1) was implicated. Multicopy suppression identified KSS1 as a suppressor and Kss1 was shown to physically interact with Cdc37, supporting a model where Cdc37 modulates osmoadaptation via MAPK signaling and downstream cell-wall organization. (yang2007cdc37pisinvolved pages 1-2)
Cdc37’s functional locale is best described as the cytosolic chaperone machinery, where it forms transient Cdc37–kinase and Hsp90–Cdc37–kinase complexes. A notable mechanistic detail is that Cdc37 can be dimeric in solution but is often described as monomeric within the ternary Hsp90–Cdc37–client complex, consistent with a dynamic adaptor role during client processing. (mandal2007cdc37hasdistinct pages 1-3, verba2017howhsp90and pages 4-6)
A 2023 review emphasizes S. cerevisiae as a premier system for dissecting the Hsp90/co-chaperone network using genetic tools, systematic interaction mapping, and proteomics, enabling inference of client dependencies and pathway integration for components such as Cdc37. This reflects current practice: using yeast to connect chaperone/co-chaperone perturbations to signaling outputs and drug responses. (Backe et al., 2023-09-01, https://doi.org/10.1042/ebc20220224) (backe2023saccharomycescerevisiaeas pages 12-13)
Yeast systems are also used as functional screening platforms to identify small molecules that perturb the Hsp90–Cdc37 pathway, commonly employing Cdc37-dependent kinase clients (e.g., sensitized Cdc28 backgrounds) as readouts and orthogonal assays for PPI disruption versus direct Hsp90 inhibition. This illustrates translational relevance (tool compounds, antifungal/anticancer target discovery) while leveraging yeast genetics for mechanism-of-action deconvolution. (guimaraes2022developmentofa pages 1-8, guimaraes2022developmentofa pages 63-66)
A highly cited expert review frames the Hsp90–Cdc37 system as enabling kinases to traverse conformational/energetic barriers (e.g., maintaining partially unfolded, activation-competent intermediates) and highlights open mechanistic questions such as how remodeling steps are coordinated with ATPase timing and co-chaperone exchange. This perspective supports interpreting yeast CDC37 phenotypes as resulting from failures in client loading, conformational stabilization, and maturation timing, rather than a single static binding defect. (Verba & Agard, 2017-10-01, https://doi.org/10.1016/j.tibs.2017.07.002) (verba2017howhsp90and pages 4-6)
CDC37 encodes an essential cytosolic Hsp90 co-chaperone that acts as a kinase-targeting adaptor. Its primary molecular role is to protect newly synthesized kinases from degradation and promote their Hsp90-dependent maturation, thereby maintaining cellular kinase abundance and enabling signaling and cell-cycle progression (notably via Cdc28 and Cak1). CDC37 function is regulated by CK2-dependent phosphorylation of conserved N-terminal serines (Ser14/Ser17 in yeast), and CDC37 also contributes to stress and osmoadaptation signaling (e.g., via Kss1-associated MAPK module crosstalk). (farrell2000cdc37promotesthe pages 1-2, mandal2007cdc37hasdistinct pages 1-3, miyata2004ck2controlsmultiple pages 1-2, yang2007cdc37pisinvolved pages 1-2)
The following table consolidates identity, molecular function, regulation, pathways, quantitative evidence, and recent application themes.
| Category | Key points | Key supporting sources with year, URL, and citation context id |
|---|---|---|
| Identity/domains | - Target matches Saccharomyces cerevisiae Cdc37, an essential Hsp90 co-chaperone specialized for protein kinases. - Domain organization is consistent with UniProt family/domain annotation: N-terminal kinase-binding region, middle Hsp90-binding region, and C-terminal region with less clearly defined but functionally contributing roles. - Yeast papers describe a conserved N-terminus important for kinase binding and regulation, with species-specific phosphosites at Ser14/Ser17. |
- Mandal et al., 2007, J Cell Biol — https://doi.org/10.1083/jcb.200604106 (mandal2007cdc37hasdistinct pages 1-3) - Verba & Agard, 2017, Trends Biochem Sci — https://doi.org/10.1016/j.tibs.2017.07.002 (verba2017howhsp90and pages 4-6) - Millson et al., 2014, Cell Stress Chaperones — https://doi.org/10.1007/s12192-014-0497-4 (millson2014cdc37engagesin pages 1-2, millson2014cdc37engagesin pages 8-9) |
| Core molecular function | - Cdc37 is a kinase-targeting adaptor/co-chaperone that recruits unstable or inactive protein kinases to Hsp90 for maturation rather than catalyzing a chemical reaction. - It protects nascent kinase chains from rapid degradation and then promotes post-translational maturation/folding with Hsp90. - Mechanistically, Cdc37 can arrest/inhibit the Hsp90 ATPase cycle during client loading by preventing lid closure and N-terminal dimerization. |
- Farrell & Morgan, 2000, Mol Cell Biol — https://doi.org/10.1128/mcb.20.3.749-754.2000 (farrell2000cdc37promotesthe pages 1-2, farrell2000cdc37promotesthe pages 5-6) - Mandal et al., 2007, J Cell Biol — https://doi.org/10.1083/jcb.200604106 (mandal2007cdc37hasdistinct pages 1-3) - Guimarães, 2022, thesis — URL not available in retrieved metadata (guimaraes2022developmentofa pages 20-25) |
| Key clients/pathways | - Best-supported yeast clients include Cdc28/CDK1 and Cak1/CDK-activating kinase, whose stability/activity depend on Cdc37. - Cdc37 broadly supports kinome biogenesis and influences signaling pathways including MAPK/cell-cycle/osmoadaptation modules; literature links it to Kss1 cross-talk control and broader MAPK regulation. - Functional impact is strongest for protein kinases rather than non-kinase substrates. |
- Farrell & Morgan, 2000, Mol Cell Biol — https://doi.org/10.1128/mcb.20.3.749-754.2000 (farrell2000cdc37promotesthe pages 1-2) - Yang et al., 2007, FEMS Yeast Res — https://doi.org/10.1111/j.1567-1364.2007.00237.x (yang2007cdc37pisinvolved pages 12-12) - Millson et al., 2014, Cell Stress Chaperones — https://doi.org/10.1007/s12192-014-0497-4 (millson2014cdc37engagesin pages 8-9) |
| Regulation/PTMs | - CK2 phosphorylation is a central regulatory mechanism; yeast Cdc37 is phosphorylated at Ser14 (and also Ser17 is discussed in yeast-focused sources), promoting productive kinase handling. - Nonphosphorylatable mutants impair kinase maturation and can destabilize much of the kinome. - PP5/Ppt1-mediated dephosphorylation in the Hsp90 complex is part of the chaperone cycle and helps regulate client activation/release. |
- Miyata & Nishida, 2004, Mol Cell Biol — https://doi.org/10.1128/mcb.24.9.4065-4074.2004 (miyata2004ck2controlsmultiple pages 1-2) - Vaughan et al., 2008, Molecular Cell — https://doi.org/10.1016/j.molcel.2008.07.021 (boczek2015thematurationofa pages 20-24, boczek2015thematurationof pages 20-24) - Millson et al., 2014, Cell Stress Chaperones — https://doi.org/10.1007/s12192-014-0497-4 (millson2014cdc37engagesin pages 1-2, millson2014cdc37engagesin pages 8-9) |
| Localization/complexes | - Cdc37 acts in the cytosolic Hsp90 chaperone machinery, forming transient Cdc37–kinase and Hsp90–Cdc37–kinase complexes. - In solution Cdc37 can dimerize, but evidence indicates it is often monomeric in the ternary Hsp90–Cdc37–client complex. - Functional localization is therefore best understood as cytosolic proteostasis/signaling complexes rather than a membrane or organellar enzyme site. |
- Mandal et al., 2007, J Cell Biol — https://doi.org/10.1083/jcb.200604106 (mandal2007cdc37hasdistinct pages 1-3) - Verba & Agard, 2017, Trends Biochem Sci — https://doi.org/10.1016/j.tibs.2017.07.002 (verba2017howhsp90and pages 4-6) - Boczek, 2015, thesis/review-like source — URL not available in retrieved metadata (boczek2015thematurationofa pages 20-24, boczek2015thematurationof pages 20-24) |
| Quantitative data | - In a survey of 65 S. cerevisiae kinases (~50% of the kinome), 51 showed decreased abundance in a cdc37 mutant, supporting a broad role in kinase homeostasis. - Review-level synthesis cited in the retrieved corpus estimates Cdc37/Hsp90 support for about ~75% of the yeast kinome and ~60% of the human kinome. - Biophysical/structural summaries report weak Cdc37 dimerization (K_D ~80 µM) and species differences in Hsp90 ATPase rates (human ~20 min⁻¹ vs yeast ~1 min⁻¹). |
- Mandal et al., 2007, J Cell Biol — https://doi.org/10.1083/jcb.200604106 (mandal2007cdc37hasdistinct pages 1-3) - Boczek, 2015, thesis/review-like source — URL not available in retrieved metadata (boczek2015thematurationofa pages 20-24, boczek2015thematurationofa pages 15-20) - Guimarães, 2022, thesis — URL not available in retrieved metadata (guimaraes2022developmentofa pages 20-25) |
| Recent developments/applications 2023-2024 | - 2023 review emphasizes S. cerevisiae as a premier model for mapping Hsp90/co-chaperone interaction networks, genetic interactions, and drug responses relevant to Cdc37-dependent kinase control. - 2024 yeast genetics further supports client/subnetwork specificity in Hsp90–cochaperone biology, reinforcing that distinct cochaperones regulate distinct client classes. - Yeast-based screening platforms have been developed to identify Hsp90–Cdc37 pathway inhibitors, using cdc28-dependent sensitization and client depletion as functional readouts. |
- Backe et al., 2023, Essays Biochem — https://doi.org/10.1042/ebc20220224 (backe2023saccharomycescerevisiaeas pages 12-13) - Fulton et al., 2024, PLOS Genet — https://doi.org/10.1371/journal.pgen.1011508 (backe2023saccharomycescerevisiaeas pages 12-13) - Guimarães, 2022, thesis with direct screening application relevant to 2023-2024 work — URL not available in retrieved metadata (guimaraes2022developmentofa pages 63-66, guimaraes2022developmentofa pages 1-8) |
Table: This table summarizes the functional annotation of Saccharomyces cerevisiae CDC37 (UniProt P06101), including identity, mechanism, pathways, regulation, localization, quantitative evidence, and recent research or application themes. It is useful as a concise evidence-backed reference for narrative reporting.
References
(farrell2000cdc37promotesthe pages 1-2): Alison Farrell and David O. Morgan. Cdc37 promotes the stability of protein kinases cdc28 and cak1. Molecular and Cellular Biology, 20:749-754, Feb 2000. URL: https://doi.org/10.1128/mcb.20.3.749-754.2000, doi:10.1128/mcb.20.3.749-754.2000. This article has 78 citations and is from a domain leading peer-reviewed journal.
(mandal2007cdc37hasdistinct pages 1-3): Atin K. Mandal, Paul Lee, Jennifer A. Chen, Nadinath Nillegoda, Alana Heller, Susan DiStasio, Handy Oen, Jacob Victor, Devi M. Nair, Jeffrey L. Brodsky, and Avrom J. Caplan. Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation. The Journal of Cell Biology, 176:319-328, Jan 2007. URL: https://doi.org/10.1083/jcb.200604106, doi:10.1083/jcb.200604106. This article has 128 citations.
(miyata2004ck2controlsmultiple pages 1-2): Yoshihiko Miyata and Eisuke Nishida. Ck2 controls multiple protein kinases by phosphorylating a kinase-targeting molecular chaperone, cdc37. Molecular and Cellular Biology, 24:4065-4074, May 2004. URL: https://doi.org/10.1128/mcb.24.9.4065-4074.2004, doi:10.1128/mcb.24.9.4065-4074.2004. This article has 184 citations and is from a domain leading peer-reviewed journal.
(millson2014cdc37engagesin pages 1-2): Stefan Millson, Patricija van Oosten-Hawle, Mohammed A. Alkuriji, Andrew Truman, Marco Siderius, and Peter W. Piper. Cdc37 engages in stable, s14a mutation-reinforced association with the most atypical member of the yeast kinome, cdk-activating kinase (cak1). Cell Stress and Chaperones, 19:695-703, Sep 2014. URL: https://doi.org/10.1007/s12192-014-0497-4, doi:10.1007/s12192-014-0497-4. This article has 5 citations and is from a peer-reviewed journal.
(verba2017howhsp90and pages 4-6): Kliment A. Verba and David A. Agard. How hsp90 and cdc37 lubricate kinase molecular switches. Trends in biochemical sciences, 42 10:799-811, Oct 2017. URL: https://doi.org/10.1016/j.tibs.2017.07.002, doi:10.1016/j.tibs.2017.07.002. This article has 120 citations and is from a domain leading peer-reviewed journal.
(verba2017howhsp90and media 39c974c8): Kliment A. Verba and David A. Agard. How hsp90 and cdc37 lubricate kinase molecular switches. Trends in biochemical sciences, 42 10:799-811, Oct 2017. URL: https://doi.org/10.1016/j.tibs.2017.07.002, doi:10.1016/j.tibs.2017.07.002. This article has 120 citations and is from a domain leading peer-reviewed journal.
(verba2017howhsp90and media fe609c0f): Kliment A. Verba and David A. Agard. How hsp90 and cdc37 lubricate kinase molecular switches. Trends in biochemical sciences, 42 10:799-811, Oct 2017. URL: https://doi.org/10.1016/j.tibs.2017.07.002, doi:10.1016/j.tibs.2017.07.002. This article has 120 citations and is from a domain leading peer-reviewed journal.
(guimaraes2022developmentofa pages 20-25): JPR Guimarães. Development of a yeast-based screening assay for inhibitors of the kinase chaperone cdc37. Unknown journal, 2022.
(farrell2000cdc37promotesthe pages 5-6): Alison Farrell and David O. Morgan. Cdc37 promotes the stability of protein kinases cdc28 and cak1. Molecular and Cellular Biology, 20:749-754, Feb 2000. URL: https://doi.org/10.1128/mcb.20.3.749-754.2000, doi:10.1128/mcb.20.3.749-754.2000. This article has 78 citations and is from a domain leading peer-reviewed journal.
(yang2007cdc37pisinvolved pages 1-2): Xiao-Xian Yang, Patricija Hawle, Jan Paul Bebelman, Annemarie Meenhuis, Marco Siderius, and Saskia M. van der Vies. Cdc37p is involved in osmoadaptation and controls high osmolarity-induced cross-talk via the map kinase kss1p. FEMS yeast research, 7 6:796-807, Sep 2007. URL: https://doi.org/10.1111/j.1567-1364.2007.00237.x, doi:10.1111/j.1567-1364.2007.00237.x. This article has 15 citations and is from a peer-reviewed journal.
(backe2023saccharomycescerevisiaeas pages 12-13): Sarah J. Backe, Mehdi Mollapour, and Mark R. Woodford. saccharomyces cerevisiae as a tool for deciphering hsp90 molecular chaperone function. Essays in Biochemistry, 67:781-795, Sep 2023. URL: https://doi.org/10.1042/ebc20220224, doi:10.1042/ebc20220224. This article has 5 citations and is from a peer-reviewed journal.
(guimaraes2022developmentofa pages 1-8): JPR Guimarães. Development of a yeast-based screening assay for inhibitors of the kinase chaperone cdc37. Unknown journal, 2022.
(guimaraes2022developmentofa pages 63-66): JPR Guimarães. Development of a yeast-based screening assay for inhibitors of the kinase chaperone cdc37. Unknown journal, 2022.
(millson2014cdc37engagesin pages 8-9): Stefan Millson, Patricija van Oosten-Hawle, Mohammed A. Alkuriji, Andrew Truman, Marco Siderius, and Peter W. Piper. Cdc37 engages in stable, s14a mutation-reinforced association with the most atypical member of the yeast kinome, cdk-activating kinase (cak1). Cell Stress and Chaperones, 19:695-703, Sep 2014. URL: https://doi.org/10.1007/s12192-014-0497-4, doi:10.1007/s12192-014-0497-4. This article has 5 citations and is from a peer-reviewed journal.
(yang2007cdc37pisinvolved pages 12-12): Xiao-Xian Yang, Patricija Hawle, Jan Paul Bebelman, Annemarie Meenhuis, Marco Siderius, and Saskia M. van der Vies. Cdc37p is involved in osmoadaptation and controls high osmolarity-induced cross-talk via the map kinase kss1p. FEMS yeast research, 7 6:796-807, Sep 2007. URL: https://doi.org/10.1111/j.1567-1364.2007.00237.x, doi:10.1111/j.1567-1364.2007.00237.x. This article has 15 citations and is from a peer-reviewed journal.
(boczek2015thematurationofa pages 20-24): E Boczek. The maturation of src kinase by the molecular chaperone hsp90 and its kinase specific cochaperone cdc37. Unknown journal, 2015.
(boczek2015thematurationof pages 20-24): E Boczek. The maturation of src kinase by the molecular chaperone hsp90 and its kinase specific cochaperone cdc37. Unknown journal, 2015.
(boczek2015thematurationofa pages 15-20): E Boczek. The maturation of src kinase by the molecular chaperone hsp90 and its kinase specific cochaperone cdc37. Unknown journal, 2015.
Exported on March 22, 2026 at 02:07 AM
Organism: Saccharomyces cerevisiae
Sequence:
MAIDYSKWDKIELSDDSDVEVHPNVDKKSFIKWKQQSIHEQRFKRNQDIKNLETQVDMYSHLNKRVDRILSNLPESSLTDLPAVTKFLNANFDKMEKSKGENVDPEIATYNEMVEDLFEQLAKDLDKEGKDSKSPSLIRDAILKHRAKIDSVTVEAKKKLDELYKEKNAHISSEDIHTGFDSSFMNKQKGGAKPLEATPSEALSSAAESNILNKLAKSSVPQTFIDFKDDPMKLAKETEEFGKISINEYSKSQKFLLEHLPIISEQQKDALMMKAFEYQLHGDDKMTLQVIHQSELMAYIKEIYDMKKIPYLNPMELSNVINMFFEKVIFNKDKPMGKESFLRSVQEKFLHIQKRSKILQQEEMDESNAEGVETIQLKSLDDSTELEVNLPDFNSKDPEEMKKVKVFKTLIPEKMQEAIMTKNLDNINKVFEDIPIEEAEKLLEVFNDIDIIGIKAILENEKDFQSLKDQYEQDHEDATMENLSLNDRDGGGDNHEEVKHTADTVD
I begin by dissecting the InterPro architecture. The polypeptide is assigned to IPR004918 (Cdc37 family, residues 1–474), establishing a dedicated co-chaperone scaffold. Its N-terminus is organized by IPR013855 (Cdc37, N-terminal domain, residues 2–183), a module typically used to engage client proteins—particularly unstable kinases. The central region carries IPR013874 (Cdc37, Hsp90 binding, residues 186–371), reinforced by IPR038189 (Cdc37, Hsp90-binding domain superfamily, residues 232–365). This central core causally defines the protein’s role: it binds and positions Hsp90 to form a productive chaperone assembly. The C-terminus is structured by IPR013873 (Cdc37, C-terminal domain, residues 388–491), a region that commonly stabilizes the co-chaperone fold and mediates additional client or cofactor contacts. The ordered layout—N-terminal client-capture domain, central Hsp90-binding engine, and C-terminal stabilizer—creates a tri-partite machine that recruits specific substrates and couples them to Hsp90-dependent folding cycles.
From this architecture, the molecular function resolves as selective protein binding. The N-terminal domain confers affinity for labile client proteins, while the central module binds Hsp90; together they enforce high-avidity interactions characteristic of co-chaperone assemblies. This supports protein binding (GO:0005515) as the operative molecular function, with binding specificity arising from coordinated recognition of both chaperone and client.
The biological process follows directly: by tethering kinase-like clients to an Hsp90-centered machine, this co-chaperone drives chaperone-mediated folding and maturation of metastable proteins. This mechanism underlies protein folding (GO:0006457), ensuring that clients attain and maintain their active conformations required for signaling and cell-cycle control.
Cellular placement is inferred from function and modularity. Such chaperone-cofactor systems operate where nascent and stress-labile proteins accumulate and where signaling hubs reside—predominantly the cytosol. The absence of transmembrane features and the soluble, multi-interface architecture point to a cytosolic environment, aligning with cytosol (GO:0005829) as the most parsimonious cellular component.
Mechanistically, the protein acts as a targeting and stabilizing hub: the N-terminal domain captures kinase-class clients; the central Hsp90-binding region docks Hsp90 and aligns ATP-driven conformational cycles; and the C-terminal domain consolidates the assembly for efficient folding. This suggests transient assemblies with Hsp90 and the Hsp70 system, and preferential handoff to kinase clients. I therefore hypothesize interactions with the core Hsp90/Hsp70 machinery and kinase substrates, forming a dynamic chaperone module that stabilizes and matures metastable signaling proteins in the cytosol.
A soluble co-chaperone that assembles with the Hsp90 system to stabilize and mature metastable client proteins—especially kinase-class substrates—in baker’s yeast. Its N-terminal module captures labile clients, a central region docks Hsp90 to drive ATP-dependent folding cycles, and the C-terminal domain consolidates the assembly. By orchestrating chaperone-mediated folding in the cytosol, it promotes the attainment and maintenance of functional conformations central to cellular signaling and proteostasis.
Co-chaperone that binds to the molecular chaperone Hsp90 and promotes the maturation of specific Hsp90 client proteins.
IPR004918, family) — residues 1-474IPR013855, domain) — residues 2-183IPR013874, domain) — residues 186-371IPR038189, homologous_superfamily) — residues 232-365IPR013873, domain) — residues 388-491Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), protein binding (GO:0005515), unfolded protein binding (GO:0051082)
Biological Process: biological_process (GO:0008150), biological regulation (GO:0065007), positive regulation of biological process (GO:0048518), response to stimulus (GO:0050896), regulation of biological process (GO:0050789), cellular process (GO:0009987), signaling (GO:0023052), response to abiotic stimulus (GO:0009628), regulation of biological quality (GO:0065008), positive regulation of signaling (GO:0023056), response to chemical (GO:0042221), positive regulation of response to stimulus (GO:0048584), cell cycle process (GO:0022402), regulation of cellular process (GO:0050794), cell cycle (GO:0007049), regulation of response to stimulus (GO:0048583), cellular response to stimulus (GO:0051716), cellular component organization or biogenesis (GO:0071840), regulation of signaling (GO:0023051), response to stress (GO:0006950), microtubule-based process (GO:0007017), cell communication (GO:0007154), signal transduction (GO:0007165), positive regulation of cellular process (GO:0048522), regulation of cell cycle (GO:0051726), positive regulation of signal transduction (GO:0009967), cellular response to environmental stimulus (GO:0104004), cellular component biogenesis (GO:0044085), intracellular signal transduction (GO:0035556), spindle pole body organization (GO:0051300), regulation of cell communication (GO:0010646), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), cellular response to abiotic stimulus (GO:0071214), regulation of signal transduction (GO:0009966), response to osmotic stress (GO:0006970), cellular component organization (GO:0016043), positive regulation of cell communication (GO:0010647), microtubule cytoskeleton organization (GO:0000226), microtubule organizing center organization (GO:0031023), regulation of protein stability (GO:0031647), cellular response to chemical stress (GO:0062197), cellular response to osmotic stress (GO:0071470), MAPK cascade (GO:0000165), osmosensory signaling pathway (GO:0007231), positive regulation of intracellular signal transduction (GO:1902533), protein stabilization (GO:0050821), organelle organization (GO:0006996), regulation of intracellular signal transduction (GO:1902531), stress-activated protein kinase signaling cascade (GO:0031098), cellular component assembly (GO:0022607), cytoskeleton organization (GO:0007010), regulation of MAPK cascade (GO:0043408), stress-activated MAPK cascade (GO:0051403), positive regulation of MAPK cascade (GO:0043410)
Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), cytoplasm (GO:0005737), intracellular anatomical structure (GO:0005622)
Generated by BioReason
Source: CDC37-bioreason-rl-predictions.md
The BioReason summary states:
A soluble co-chaperone that assembles with the Hsp90 system to stabilize and mature metastable client proteins -- especially kinase-class substrates -- in baker's yeast.
This is accurate. The curated review confirms CDC37 is an Hsp90 co-chaperone that promotes maturation of specific Hsp90 client proteins, with kinase specificity well documented (GO:0019901 protein kinase binding from GO_REF:0000002; protein stabilization GO:0050821).
Its N-terminal module captures labile clients, a central region docks Hsp90 to drive ATP-dependent folding cycles, and the C-terminal domain consolidates the assembly.
This domain-level description correctly maps to the three known CDC37 domains (IPR013855, IPR013874, IPR013873) and their functional roles.
By orchestrating chaperone-mediated folding in the cytosol, it promotes the attainment and maintenance of functional conformations central to cellular signaling and proteostasis.
Cytosolic localization is correct (multiple lines of evidence in curated review: IBA, IEA, HDA). The connection to protein folding (GO:0006457) and protein stabilization (GO:0050821) is accurate.
The summary correctly captures protein folding and protein stabilization as core functions. However, it misses several important non-core but documented functions: the requirement for passage through START in the cell cycle (GO:0051726), involvement in HOG and PKC MAP kinase signaling cascades (GO:0043410, GO:0038066), spindle pole body duplication (GO:0030474), and the cellular hyperosmotic response (GO:0071474). These are context-dependent functions documented by IMP evidence (PMID:17220467, PMID:9060463, PMID:7753858).
The molecular function is described as "selective protein binding," which the curated review marks as over-annotated when generic (GO:0005515). The more informative terms are heat shock protein binding (GO:0031072), protein-folding chaperone binding (GO:0051087), and protein kinase binding (GO:0019901).
Comparison with interpro2go:
The interpro2go annotation (GO_REF:0000002) provides protein kinase binding (GO:0019901), which is a specific and informative molecular function term. BioReason's summary describes kinase-client binding in prose but does not reach this level of specificity in its GO term predictions -- it outputs only protein binding (GO:0005515) and unfolded protein binding (GO:0051082) as MF terms, both of which the curated review marks as over-annotated. BioReason adds narrative value about the tri-partite domain architecture and mechanism but does not improve on interpro2go for functional specificity.
The trace correctly identifies the three-domain architecture and its functional implications. The reasoning from domain structure to co-chaperone function is sound. The prediction of Hsp70 system cooperation is reasonable but the specific downstream signaling roles (MAPK cascades, cell cycle) are entirely absent from the reasoning, which stays at the level of generic chaperone biology.
id: P06101
gene_symbol: CDC37
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:559292
label: Saccharomyces cerevisiae
description: >-
CDC37 encodes an essential cytosolic Hsp90 co-chaperone that specializes the
Hsp90 system for protein kinase clients. Cdc37 binds protein kinases and Hsp90,
promotes Hsp90-kinase complex formation, protects nascent kinase chains from
rapid degradation, and supports post-translational kinase maturation. Its
client effects explain downstream roles in Cdc28/Cak1-dependent cell-cycle
progression, MAP kinase signaling, osmotic and cell wall stress responses, and
spindle pole body duplication, but the core function is kinase-specific
chaperone/adaptor activity rather than those downstream pathways themselves.
existing_annotations:
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
The phylogenetic cytoplasm annotation is consistent with experimental
localization and with Cdc37 acting in cytosolic Hsp90-kinase complexes.
action: ACCEPT
reason: >-
Cdc37 is experimentally detected in the cytoplasm and its core Hsp90
co-chaperone activity is carried out in the cytosolic chaperone machinery.
supported_by:
- reference_id: PMID:14562095
supporting_text: Global analysis of protein localization in budding yeast.
- reference_id: file:yeast/CDC37/CDC37-deep-research-falcon.md
supporting_text: >-
Cdc37's functional locale is best described as the cytosolic chaperone
machinery, where it forms transient Cdc37-kinase and
Hsp90-Cdc37-kinase complexes.
- term:
id: GO:0006457
label: protein folding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
Cdc37 is a kinase-directed Hsp90 co-chaperone required for productive
folding and maturation of protein kinases.
action: ACCEPT
reason: >-
Although Cdc37 is not a general foldase for all proteins, the annotation
accurately captures its core role in protein kinase folding/maturation in
the Hsp90 pathway.
supported_by:
- reference_id: PMID:17242065
supporting_text: >-
Cdc37 functions at distinct steps in kinase biogenesis that involves
protecting nascent chains from rapid degradation followed by its folding
function in association with Hsp90.
- reference_id: file:yeast/CDC37/CDC37-deep-research-falcon.md
supporting_text: >-
Cdc37 selectively recognizes kinase clients and promotes their
stabilization and productive engagement with Hsp90 to achieve
folding/maturation and functional activation.
- term:
id: GO:0031072
label: heat shock protein binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
The annotation reflects the well-established physical and functional
interaction between Cdc37 and Hsp90.
action: ACCEPT
reason: >-
Hsp90 binding is central to Cdc37 function as a kinase-targeting adaptor
and is supported by biochemical and genetic evidence for Hsp90-Cdc37-kinase
complexes.
supported_by:
- reference_id: PMID:9242486
supporting_text: >-
The identification of Cdc37 as the 50-kD protein in several Hsp90-kinase
complexes, together with other data, led to the recent suggestion that
Cdc37 is a kinase-targeting "subunit" of Hsp90.
- reference_id: PMID:17220467
supporting_text: >-
The interaction of Hsp90, Slt2p, and Hog1p with Cdc37p depends on the
phosphorylation status of Cdc37p.
- term:
id: GO:0050821
label: protein stabilization
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
Protein stabilization is a core biological process for Cdc37, specifically
stabilization of protein kinase clients.
action: ACCEPT
reason: >-
Multiple studies show that Cdc37 maintains kinase abundance and protects
newly synthesized kinases from degradation.
supported_by:
- reference_id: PMID:17242065
supporting_text: >-
showed that 51 had decreased abundance compared with levels in the
wild-type strain.
- reference_id: file:yeast/CDC37/CDC37-deep-research-falcon.md
supporting_text: >-
In a panel of 65 kinases, 51 showed decreased abundance in a cdc37
mutant, supporting a broad role in kinase homeostasis.
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
Cdc37 does bind non-native kinase clients, but the broad "unfolded protein
binding" term obscures the kinase-specific co-chaperone mechanism.
action: MODIFY
reason: >-
Replace the generic binding term with protein-folding chaperone activity;
kinase client binding is already captured by the accepted GO:0019901 annotation.
proposed_replacement_terms:
- id: GO:0044183
label: protein folding chaperone
supported_by:
- reference_id: PMID:17242065
supporting_text: >-
Cdc37 protects nascent kinase chains from rapid degradation shortly
after synthesis.
- term:
id: GO:0051087
label: protein-folding chaperone binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: >-
This term captures Cdc37 binding to the Hsp90 chaperone machinery.
action: ACCEPT
reason: >-
Protein-folding chaperone binding is a core molecular interaction for
Cdc37, which couples kinase clients to Hsp90.
supported_by:
- reference_id: PMID:9242486
supporting_text: >-
the very similar chaperone activities of the two proteins, uncovered
through in vitro analysis, diverge in vivo in specific signal
transduction pathways.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: >-
UniProtKB subcellular-location mapping to cytoplasm is correct.
action: ACCEPT
reason: >-
The automated cytoplasm annotation agrees with the experimental
localization and the cytosolic Hsp90 co-chaperone function.
supported_by:
- reference_id: UniProt:P06101
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm.'
- term:
id: GO:0019901
label: protein kinase binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: >-
InterPro-derived protein kinase binding is highly specific and captures
the key client-recognition activity of Cdc37.
action: ACCEPT
reason: >-
Cdc37 is a kinase-targeting co-chaperone, and protein kinase binding is
the most informative currently annotated molecular function for its client
specificity.
supported_by:
- reference_id: UniProt:P06101
supporting_text: >-
Co-chaperone that binds to numerous kinases and promotes their
interaction with the Hsp90 complex, resulting in their stabilization.
- reference_id: file:yeast/CDC37/CDC37-deep-research-falcon.md
supporting_text: >-
Cdc37 selectively recognizes kinase clients and promotes their
stabilization and productive engagement with Hsp90.
- term:
id: GO:0051301
label: cell division
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: >-
Cell division is a true consequence of Cdc37 activity through Cdc28/Cak1
and spindle-pole-body kinase clients, but it is not the molecular core
function of Cdc37.
action: KEEP_AS_NON_CORE
reason: >-
Retain as a supported downstream biological process while keeping the core
function focused on kinase-specific chaperoning and stabilization.
supported_by:
- reference_id: PMID:7753858
supporting_text: Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins.
- reference_id: file:yeast/CDC37/CDC37-deep-research-falcon.md
supporting_text: >-
CDC37 is essential for G1/Start progression and for activation of the
major cyclin-dependent kinase Cdc28.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15766533
review:
summary: >-
This high-throughput interaction annotation is real evidence of physical
interactions but the term is too generic for Cdc37.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Protein binding does not distinguish Cdc37's specific Hsp90/kinase
co-chaperone role; specific kinase and chaperone binding annotations are
more informative.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15879519
review:
summary: >-
The interaction evidence supports Hsp90 pathway biology but the generic
protein binding term is uninformative.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Use specific Hsp90/chaperone and kinase-client terms rather than generic
protein binding for Cdc37.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16554755
review:
summary: >-
Large-scale complex data document interactions but do not by themselves
define a specific molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Generic protein binding is over-annotated for a co-chaperone whose
specific binding modes are captured by protein kinase binding and
protein-folding chaperone binding.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19536198
review:
summary: >-
The chaperone-protein interaction atlas supports Cdc37 involvement in the
chaperone network, but the GO term is too broad.
action: MARK_AS_OVER_ANNOTATED
reason: >-
The annotation should not be treated as core because more specific
chaperone and kinase-client binding terms describe the function.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: HDA
original_reference_id: PMID:14562095
review:
summary: >-
High-throughput localization to cytoplasm agrees with the known site of
Cdc37-Hsp90 kinase-chaperone action.
action: ACCEPT
reason: >-
Cytoplasm is a supported core cellular component for Cdc37.
- term:
id: GO:0043410
label: positive regulation of MAPK cascade
evidence_type: IMP
original_reference_id: PMID:17220467
review:
summary: >-
Cdc37 positively affects HOG and PKC MAPK pathway output by stabilizing
and interacting with Hog1 and Slt2.
action: KEEP_AS_NON_CORE
reason: >-
This is well-supported pathway-level biology but is downstream of the
core kinase-chaperone function.
supported_by:
- reference_id: PMID:17220467
supporting_text: >-
levels of the MAPKs Hog1p and Slt2p (Mpk1p) in cells are reduced in a
cdc37-S14A mutant
- term:
id: GO:0071474
label: cellular hyperosmotic response
evidence_type: IMP
original_reference_id: PMID:17220467
review:
summary: >-
The hyperosmotic-response phenotype is supported by cdc37-S14A effects on
Hog1/Hsp90/Cdc37 interactions.
action: KEEP_AS_NON_CORE
reason: >-
Retain as a valid stress-response annotation, but do not elevate it above
the kinase-specific chaperone role.
supported_by:
- reference_id: PMID:17220467
supporting_text: >-
Mutation of the phosphorylation site Ser14 in Cdc37p renders cells
sensitive to osmotic stress.
- term:
id: GO:0071852
label: fungal-type cell wall organization or biogenesis
evidence_type: IMP
original_reference_id: PMID:17220467
review:
summary: >-
Cdc37 affects cell wall stress responses through the Slt2/PKC MAPK pathway.
action: KEEP_AS_NON_CORE
reason: >-
This is a supported downstream pathway consequence of kinase chaperoning,
not the core molecular role.
supported_by:
- reference_id: PMID:17220467
supporting_text: >-
during cell wall stress, the interaction of Slt2p with Cdc37p and Hsp90
is crucial for Slt2p-dependent downstream responses
- term:
id: GO:0038066
label: p38MAPK cascade
evidence_type: IPI
original_reference_id: PMID:17220467
review:
summary: >-
In yeast this annotation reflects Hog1 MAPK interaction and pathway
support by Cdc37.
action: KEEP_AS_NON_CORE
reason: >-
The physical interaction is relevant but represents a client/pathway
context rather than the core function of Cdc37.
supported_by:
- reference_id: PMID:17220467
supporting_text: >-
Hog1p and Slt2p both interact in a complex with Cdc37p in vivo.
- term:
id: GO:0071474
label: cellular hyperosmotic response
evidence_type: IPI
original_reference_id: PMID:17220467
review:
summary: >-
Interaction with Hog1 supports Cdc37 participation in osmotic stress
signaling.
action: KEEP_AS_NON_CORE
reason: >-
The annotation is valid as pathway context but should remain non-core
relative to the kinase-chaperone activity.
supported_by:
- reference_id: PMID:17220467
supporting_text: >-
the osmosensitive phenotype of the cdc37-S14A mutant is due to the loss
of the interaction between Cdc37p, Hog1p, and Hsp90.
- term:
id: GO:0030474
label: spindle pole body duplication
evidence_type: IMP
original_reference_id: PMID:9060463
review:
summary: >-
Cdc37 is required for proper spindle pole body duplication, likely through
kinase-client biology involving Mps1.
action: KEEP_AS_NON_CORE
reason: >-
Retain as a supported cell-cycle phenotype, but classify as non-core
because it is downstream of Cdc37's kinase-chaperone role.
supported_by:
- reference_id: PMID:9060463
supporting_text: The yeast CDC37 gene interacts with MPS1 and is required for proper execution of spindle pole body duplication.
- term:
id: GO:0050821
label: protein stabilization
evidence_type: IMP
original_reference_id: PMID:17242065
review:
summary: >-
This annotation directly captures the experimentally demonstrated role of
Cdc37 in kinase abundance and nascent-chain quality control.
action: ACCEPT
reason: >-
Protein stabilization of kinase clients is central to Cdc37 function.
supported_by:
- reference_id: PMID:17242065
supporting_text: >-
Results from our pulse-labeling studies showed that Cdc37 protects
nascent kinase chains from rapid degradation shortly after synthesis.
- term:
id: GO:0051082
label: unfolded protein binding
evidence_type: IDA
original_reference_id: PMID:9242486
review:
summary: >-
The experiment supports molecular chaperone activity, but the GO term is
too generic for Cdc37's kinase-directed function.
action: MODIFY
reason: >-
Replace generic unfolded protein binding with protein folding chaperone,
while leaving protein kinase binding to the existing accepted GO:0019901 annotation.
proposed_replacement_terms:
- id: GO:0044183
label: protein folding chaperone
supported_by:
- reference_id: PMID:9242486
supporting_text: >-
In vitro, Cdc37 maintains denatured beta-galactosidase in an
activation-competent state without reactivating it and stabilizes
mature, but unstable, casein kinase II.
- term:
id: GO:0051726
label: regulation of cell cycle
evidence_type: IMP
original_reference_id: PMID:7753858
review:
summary: >-
Cdc37 regulates cell-cycle progression through effects on the cyclin-
dependent kinase Cdc28.
action: KEEP_AS_NON_CORE
reason: >-
Cell-cycle regulation is an important downstream consequence of kinase
chaperoning but should not be treated as the primary molecular function.
supported_by:
- reference_id: PMID:7753858
supporting_text: Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: PMID:14562095
title: Global analysis of protein localization in budding yeast.
findings: []
- id: PMID:15766533
title: 'Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone.'
findings: []
- id: PMID:15879519
title: A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p).
findings: []
- id: PMID:16554755
title: Global landscape of protein complexes in the yeast Saccharomyces cerevisiae.
findings: []
- id: PMID:17220467
title: Cdc37p is required for stress-induced high-osmolarity glycerol and protein kinase C mitogen-activated protein kinase pathway functionality by interaction with Hog1p and Slt2p (Mpk1p).
findings:
- statement: Cdc37 supports HOG and PKC MAPK signaling by stabilizing/interacting with Hog1 and Slt2.
supporting_text: >-
Levels of the MAPKs Hog1p and Slt2p in cells are reduced in a
cdc37-S14A mutant, and downstream responses mediated by Hog1p and Slt2p
are compromised.
- id: PMID:17242065
title: Cdc37 has distinct roles in protein kinase quality control that protect nascent chains from degradation and promote posttranslational maturation.
findings:
- statement: Cdc37 broadly stabilizes the yeast kinome.
supporting_text: >-
Analysis of 65 Saccharomyces cerevisiae protein kinases showed that 51 had
decreased abundance compared with levels in the wild-type strain.
- statement: Cdc37 protects nascent kinase chains from rapid degradation.
supporting_text: >-
Results from pulse-labeling studies showed that Cdc37 protects nascent
kinase chains from rapid degradation shortly after synthesis.
- id: PMID:19536198
title: 'An atlas of chaperone-protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell.'
findings: []
- id: PMID:7753858
title: Cdc37 is required for association of the protein kinase Cdc28 with G1 and mitotic cyclins.
findings: []
- id: PMID:9060463
title: The yeast CDC37 gene interacts with MPS1 and is required for proper execution of spindle pole body duplication.
findings: []
- id: PMID:9242486
title: Cdc37 is a molecular chaperone with specific functions in signal transduction.
findings:
- statement: Cdc37 has intrinsic chaperone activity and stabilizes kinase clients.
supporting_text: >-
In vitro, Cdc37 maintains denatured beta-galactosidase in an
activation-competent state without reactivating it and stabilizes mature,
but unstable, casein kinase II.
- id: UniProt:P06101
title: UniProt entry for CDC37/Hsp90 co-chaperone Cdc37
findings:
- statement: UniProt summarizes Cdc37 as a kinase-binding Hsp90 co-chaperone.
supporting_text: >-
Co-chaperone that binds to numerous kinases and promotes their interaction
with the Hsp90 complex, resulting in their stabilization.
- id: file:yeast/CDC37/CDC37-deep-research-falcon.md
title: Falcon deep research report for CDC37
findings:
- statement: Falcon synthesis supports kinase-specific Hsp90 co-chaperone function as the core role.
supporting_text: >-
CDC37 encodes an essential cytosolic Hsp90 co-chaperone that acts as a
kinase-targeting adaptor.
- id: file:interpro/panther/PTHR12800/PTHR12800-metadata.yaml
title: PANTHER family PTHR12800 CDC37-related metadata
findings:
- statement: PTHR12800 places yeast Cdc37 in the conserved CDC37-related family.
supporting_text: PANTHER family PTHR12800 is named CDC37-RELATED and includes the HSP90 co-chaperone CDC37 subfamily.
core_functions:
- molecular_function:
id: GO:0019901
label: protein kinase binding
directly_involved_in:
- id: GO:0006457
label: protein folding
- id: GO:0050821
label: protein stabilization
locations:
- id: GO:0005737
label: cytoplasm
description: >-
Cdc37 is the kinase-targeting adaptor of the cytosolic Hsp90 chaperone
system. It binds nascent or unstable protein kinase clients, protects many
kinases from rapid degradation, and promotes subsequent Hsp90-dependent
maturation. This client-specific chaperone role explains broad effects on
Cdc28/Cak1 cell-cycle control, MAPK signaling, and spindle-pole-body
duplication without making those downstream pathways the core function.
supported_by:
- reference_id: PMID:17242065
supporting_text: >-
showed that 51 had decreased abundance compared with levels in the
wild-type strain.
- reference_id: PMID:17242065
supporting_text: >-
Cdc37 functions at distinct steps in kinase biogenesis that involves
protecting nascent chains from rapid degradation followed by its folding
function in association with Hsp90.
- reference_id: file:yeast/CDC37/CDC37-deep-research-falcon.md
supporting_text: >-
Cdc37 selectively recognizes kinase clients and promotes their
stabilization and productive engagement with Hsp90 to achieve
folding/maturation and functional activation.
- reference_id: file:interpro/panther/PTHR12800/PTHR12800-metadata.yaml
supporting_text: PANTHER family PTHR12800 is named CDC37-RELATED and includes the HSP90 co-chaperone CDC37 subfamily.
- molecular_function:
id: GO:0044183
label: protein folding chaperone
directly_involved_in:
- id: GO:0006457
label: protein folding
- id: GO:0050821
label: protein stabilization
locations:
- id: GO:0005737
label: cytoplasm
description: >-
Cdc37 has a kinase-directed chaperone/stabilizing activity: it protects
nascent or unstable kinase clients and keeps them competent for subsequent
Hsp90-dependent maturation. This captures the GO:0044183 replacement used for
broad unfolded-protein-binding annotations without treating Cdc37 as a generic
bulk-folding chaperone.
supported_by:
- reference_id: PMID:17242065
supporting_text: >-
Cdc37 protects nascent kinase chains from rapid degradation shortly after
synthesis.
- reference_id: PMID:9242486
supporting_text: >-
In vitro, Cdc37 maintains denatured beta-galactosidase in an
activation-competent state without reactivating it and stabilizes mature,
but unstable, casein kinase II.
- molecular_function:
id: GO:0051087
label: protein-folding chaperone binding
directly_involved_in:
- id: GO:0006457
label: protein folding
locations:
- id: GO:0005737
label: cytoplasm
description: >-
Cdc37 binds the Hsp90 protein-folding chaperone system and helps load kinase
clients into Hsp90-containing maturation complexes. This Hsp90-binding
adaptor role is an inseparable part of the core kinase co-chaperone
mechanism.
supported_by:
- reference_id: PMID:9242486
supporting_text: >-
The identification of Cdc37 as the 50-kD protein in several Hsp90-kinase
complexes, together with other data, led to the recent suggestion that
Cdc37 is a kinase-targeting "subunit" of Hsp90.
- reference_id: PMID:17220467
supporting_text: >-
Hog1p and Slt2p both interact in a complex with Cdc37p in vivo.
proposed_new_terms: []
suggested_questions:
- question: >-
Which yeast kinase clients require Cdc37 primarily for nascent-chain
stabilization versus later Hsp90-dependent maturation?
- question: >-
Are there yeast stress conditions that shift Cdc37 client specificity beyond
the kinases already surveyed by abundance and interaction assays?
suggested_experiments:
- experiment_type: quantitative proteomics
hypothesis: >-
Distinct kinase subclasses show different dependence on Cdc37 for
nascent-chain stabilization versus post-translational maturation.
description: >-
Pulse-SILAC or equivalent time-resolved proteomics in phosphosite and
temperature-sensitive cdc37 mutants, paired with kinase activity assays, to
separate defects in kinase synthesis, stability, and maturation.