CDC37L1 (Hsp90 co-chaperone Cdc37-like 1, also called Harc, "Hsp90-associating relative of Cdc37") is a cytoplasmic co-chaperone of the CDC37 family and a paralog of the kinase-specific Hsp90 co-chaperone CDC37. It self-associates and forms complexes with the molecular chaperones Hsp70 and Hsp90 as well as with Hsp90 co-chaperones and adaptors including CDC37, STIP1/Hop, FKBP4 and PPID. Through distinct domains it engages Hsp90 (central/C-terminal region) and Hsp70/Hop (C-terminal region), acting as an adaptor that promotes the interaction of client proteins with the Hsp70 and Hsp90 chaperone systems and thereby contributing to client (notably protein kinase) folding, maturation and stabilization. It is broadly expressed (brain, heart, kidney, liver, placenta and skeletal muscle) and is phosphorylated on serine residues.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: CDC37L1 is a cytoplasmic co-chaperone; cytoplasmic localization is well supported experimentally and by phylogenetic inference across the CDC37 family. Reason: The cytoplasm is where CDC37L1 acts as an Hsp70/Hsp90 co-chaperone. This IBA localization is corroborated by direct experimental evidence (PubMed:11413142 subcellular location; HPA IDA cytosol). Supporting Evidence: file:human/CDC37L1/CDC37L1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006457 protein folding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CDC37L1 contributes to chaperone-mediated client protein folding/maturation as a co-chaperone of the Hsp70/Hsp90 system. Protein folding is a reasonable biological-process outcome of this co-chaperone role, though CDC37L1's direct molecular action is adaptor/co-chaperone binding rather than catalysis of folding itself. Reason: The protein folding process is a downstream consequence of the Hsp70/Hsp90 machine that CDC37L1 supports as a co-chaperone; it is a plausible process annotation but is non-core relative to its molecular co-chaperone/adaptor function. Supporting Evidence: file:human/CDC37L1/CDC37L1-uniprot.txt Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90. |
| GO:0031072 heat shock protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: CDC37L1 binds the heat shock proteins Hsp90 and Hsp70 directly, forming complexes with both. This is the core molecular function of CDC37L1 as a co-chaperone. Reason: Direct, experimentally documented binding to HSP90 (HSP90AA1/HSP90AB1) and HSP70 supports this molecular function term; it is central to CDC37L1's role. Supporting Evidence: file:human/CDC37L1/CDC37L1-uniprot.txt Self-associates. Forms complexes with Hsp70 and Hsp90. |
| GO:0050821 protein stabilization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: As an Hsp70/Hsp90 co-chaperone, CDC37L1 participates in stabilizing client proteins during their maturation. This is a plausible biological-process outcome of the co-chaperone role but is a downstream effect rather than CDC37L1's direct function. Reason: Protein stabilization is an outcome of the chaperone machine CDC37L1 assists; it is a reasonable non-core process annotation inherited by phylogenetic transfer within the CDC37 family. Supporting Evidence: file:human/CDC37L1/CDC37L1-uniprot.txt Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90. |
| GO:0051087 protein-folding chaperone binding | IBA GO_REF:0000033 | ACCEPT | Summary: CDC37L1 binds the molecular chaperones Hsp90 and Hsp70 (and the Hsp70/Hsp90 adaptor STIP1/Hop and the paralog CDC37), consistent with its role as a co-chaperone that engages the folding-chaperone machinery. Reason: Binding to Hsp90, Hsp70 and Hop/STIP1 is directly documented experimentally and is core to the co-chaperone adaptor function. Supporting Evidence: file:human/CDC37L1/CDC37L1-uniprot.txt Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization, redundant with but consistent with the experimentally supported and IBA cytoplasm annotations. Reason: Correct localization for this cytoplasmic co-chaperone; although derived from an automated IEA pipeline, it agrees with stronger experimental/IBA evidence for the same compartment. Supporting Evidence: file:human/CDC37L1/CDC37L1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MODIFY | Summary: High-throughput human liver interactome screen capturing a CDC37L1-HSP90AB1 interaction. The bare "protein binding" term is uninformative; the specific HSP90 binding it reflects is better captured by Hsp90 protein binding. Reason: Per curation guidelines, bare protein binding (GO:0005515) is uninformative. The IntAct WITH partner here is HSP90AB1 (P08238), so the interaction is more precisely captured by Hsp90 protein binding (GO:0051879). Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005515 protein binding IPI PMID:21988832 WITH UniProtKB:P08238 |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | MODIFY | Summary: Quantitative chaperone interaction network (Taipale et al.) placing CDC37L1 within the Hsp90 co-chaperone module, with WITH partners HSP90AA1, HSP90AB1 and STIP1/Hop. The bare protein binding term is uninformative; the biologically meaningful interactions are with Hsp90 (and the Hop adaptor). Reason: Bare protein binding is uninformative. The most biologically relevant partners captured here are HSP90AA1 (P07900) and HSP90AB1 (P08238), so Hsp90 protein binding (GO:0051879) is the appropriate specific molecular function. Proposed replacements: Hsp90 protein binding Supporting Evidence: PMID:25036637 surveying the physical interaction landscape of all known Hsp90 co-chaperones and several known Hsp70 cochaperones file:human/CDC37L1/CDC37L1-goa.tsv GO:0005515 protein binding IPI PMID:25036637 WITH UniProtKB:P07900 / P08238 / P31948 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Large-scale yeast two-hybrid human interactome screen capturing a CDC37L1-HSP90AB1 interaction. The bare protein binding term is uninformative. Reason: Bare protein binding is uninformative. The WITH partner is HSP90AB1 (P08238), so Hsp90 protein binding (GO:0051879) is the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005515 protein binding IPI PMID:25416956 WITH UniProtKB:P08238 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Neurodegeneration interactome screen capturing a CDC37L1-BRK1 (Q8WUW1) interaction. This is an isolated high-throughput interaction with a non-chaperone partner and does not inform CDC37L1's core co-chaperone function. Reason: Bare protein binding from a single high-throughput screen with a partner (BRK1, a WAVE/SCAR-complex component) unrelated to CDC37L1's chaperone function; uninformative and not part of the core function. Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005515 protein binding IPI PMID:32814053 WITH UniProtKB:Q8WUW1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: BioPlex affinity-purification interactome (Huttlin et al.) capturing CDC37L1 interactions with HSP90AA1 and HSP90AB1. The bare protein binding term is uninformative; the relevant interactions are with Hsp90. Reason: Bare protein binding is uninformative. The WITH partners are HSP90AA1 (P07900) and HSP90AB1 (P08238), so Hsp90 protein binding (GO:0051879) is the appropriate specific molecular function. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005515 protein binding IPI PMID:33961781 WITH UniProtKB:P07900 / P08238 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: Multimodal cell-maps interactome study capturing a CDC37L1-HSP90AB1 interaction. The bare protein binding term is uninformative; the interaction reflects Hsp90 binding. Reason: Bare protein binding is uninformative. The WITH partner is HSP90AB1 (P08238), so Hsp90 protein binding (GO:0051879) is the appropriate specific term. Proposed replacements: Hsp90 protein binding Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005515 protein binding IPI PMID:40205054 WITH UniProtKB:P08238 |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence evidence (HPA) for cytosolic localization, consistent with CDC37L1's role as a cytoplasmic co-chaperone. Reason: IDA-supported cytosolic localization agrees with the documented cytoplasmic site of action and is a precise cellular-component annotation. Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005829 cytosol IDA GO_REF:0000052 HPA |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-481009 | KEEP AS NON CORE | Summary: Reactome annotation derived from detection of CDC37L1 in platelet dense granule releasate/exocytosis. This reflects a specialized platelet-biology context, not CDC37L1's core cytoplasmic co-chaperone function. Reason: Curated TAS localization from platelet degranulation proteomics; plausible but peripheral to the gene's core function and at odds with its primary cytoplasmic site of action. Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0005576 extracellular region TAS Reactome:R-HSA-481009 |
| GO:0031089 platelet dense granule lumen | TAS Reactome:R-HSA-481009 | KEEP AS NON CORE | Summary: Reactome annotation placing CDC37L1 in the platelet dense granule lumen based on platelet exocytosis pathway curation. This is a specialized context distinct from its core cytoplasmic chaperone role. Reason: Curated TAS localization from platelet biology; retained as non-core because it is peripheral to and does not reflect CDC37L1's principal cytoplasmic co-chaperone function. Supporting Evidence: file:human/CDC37L1/CDC37L1-goa.tsv GO:0031089 platelet dense granule lumen TAS Reactome:R-HSA-481009 |
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Download this section (compressed HTML)Q: Does CDC37L1/Harc have a kinase-client specificity distinct from its paralog CDC37, or does it act redundantly within the Hsp90 kinase-maturation pathway?
Q: Is the platelet dense granule / extracellular localization of CDC37L1 a genuine secreted pool with a function, or carryover from abundant cytoplasmic chaperome proteins in platelet proteomics?
Q: What is the functional consequence of CDC37L1 phosphorylation at Ser-32 (mitotic / TCR signaling) and Ser-88 for its chaperone-binding or client-handoff activity?
Experiment: Affinity purification-mass spectrometry of tagged CDC37L1 versus CDC37 from the same cell line to compare their kinase-client repertoires and define CDC37L1-specific clients.
Experiment: In vitro reconstitution assays measuring CDC37L1-dependent loading of a model kinase client onto Hsp90 (and handoff from Hsp70/Hop), using the C-terminal Hsp70-binding and central Hsp90-binding regions as domain deletions.
Experiment: CRISPR knockout or knockdown of CDC37L1 (with and without CDC37 co-depletion) followed by kinome stability profiling to test for redundancy with CDC37 in client maturation.
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