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 and cell wall perturbation by calcofluor white. |
| 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. |
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Download this section (compressed HTML)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
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