id: Q7L3B6 gene_symbol: CDC37L1 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 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. existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: CDC37L1 is a cytoplasmic co-chaperone; cytoplasmic localization is well supported experimentally and by phylogenetic inference across the CDC37 family. action: ACCEPT 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). supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0006457 label: protein folding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90. - term: id: GO:0031072 label: heat shock protein binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT reason: Direct, experimentally documented binding to HSP90 (HSP90AA1/HSP90AB1) and HSP70 supports this molecular function term; it is central to CDC37L1's role. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Self-associates. Forms complexes with Hsp70 and Hsp90. - term: id: GO:0050821 label: protein stabilization evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90. - term: id: GO:0051087 label: protein-folding chaperone binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: 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. action: ACCEPT reason: Binding to Hsp90, Hsp70 and Hop/STIP1 is directly documented experimentally and is core to the co-chaperone adaptor function. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic annotation of cytoplasmic localization, redundant with but consistent with the experimentally supported and IBA cytoplasm annotations. action: ACCEPT 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. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21988832 qualifier: enables review: 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. action: MODIFY 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_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:21988832 WITH UniProtKB:P08238 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25036637 qualifier: enables review: 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). action: MODIFY 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_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: PMID:25036637 supporting_text: surveying the physical interaction landscape of all known Hsp90 co-chaperones and several known Hsp70 cochaperones - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:25036637 WITH UniProtKB:P07900 / P08238 / P31948 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Large-scale yeast two-hybrid human interactome screen capturing a CDC37L1-HSP90AB1 interaction. The bare protein binding term is uninformative. action: MODIFY reason: Bare protein binding is uninformative. The WITH partner is HSP90AB1 (P08238), so Hsp90 protein binding (GO:0051879) is the appropriate specific term. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:25416956 WITH UniProtKB:P08238 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: 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. action: MARK_AS_OVER_ANNOTATED 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. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:32814053 WITH UniProtKB:Q8WUW1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: 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. action: MODIFY 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_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:33961781 WITH UniProtKB:P07900 / P08238 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome study capturing a CDC37L1-HSP90AB1 interaction. The bare protein binding term is uninformative; the interaction reflects Hsp90 binding. action: MODIFY reason: Bare protein binding is uninformative. The WITH partner is HSP90AB1 (P08238), so Hsp90 protein binding (GO:0051879) is the appropriate specific term. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI PMID:40205054 WITH UniProtKB:P08238 - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence evidence (HPA) for cytosolic localization, consistent with CDC37L1's role as a cytoplasmic co-chaperone. action: ACCEPT reason: IDA-supported cytosolic localization agrees with the documented cytoplasmic site of action and is a precise cellular-component annotation. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005829 cytosol IDA GO_REF:0000052 HPA - term: id: GO:0005576 label: extracellular region evidence_type: TAS original_reference_id: Reactome:R-HSA-481009 qualifier: located_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005576 extracellular region TAS Reactome:R-HSA-481009 - term: id: GO:0031089 label: platelet dense granule lumen evidence_type: TAS original_reference_id: Reactome:R-HSA-481009 qualifier: located_in review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0031089 platelet dense granule lumen TAS Reactome:R-HSA-481009 references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:21988832 title: Toward an understanding of the protein interaction network of the human liver. findings: - statement: High-throughput liver interactome screen capturing a CDC37L1-HSP90AB1 interaction. reference_section_type: RESULTS - id: PMID:25036637 title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. findings: - statement: Systematic LUMIER/AP-MS survey of all known Hsp90 co-chaperones and several Hsp70 co-chaperones in human cells, placing CDC37L1 with HSP90AA1, HSP90AB1 and STIP1. reference_section_type: RESULTS - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: Yeast two-hybrid human interactome map capturing a CDC37L1-HSP90AB1 interaction. reference_section_type: RESULTS - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: - statement: Neurodegeneration-focused interactome screen capturing a CDC37L1-BRK1 interaction. reference_section_type: RESULTS - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: - statement: BioPlex affinity-purification interactome capturing CDC37L1 interactions with HSP90AA1 and HSP90AB1. reference_section_type: RESULTS - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: - statement: Multimodal cell-maps interactome capturing a CDC37L1-HSP90AB1 interaction. reference_section_type: RESULTS - id: Reactome:R-HSA-481009 title: Exocytosis of platelet dense granule content findings: [] - id: file:human/CDC37L1/CDC37L1-uniprot.txt title: UniProt entry Q7L3B6 (CD37L_HUMAN), Hsp90 co-chaperone Cdc37-like 1 findings: - statement: Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90; self-associates and forms complexes with Hsp70 and Hsp90; interacts with CDC37, FKBP4, PPID and STIP1; cytoplasmic; member of the CDC37 family. reference_section_type: OTHER core_functions: - description: HSP90 co-chaperone / chaperone-binding adaptor that binds Hsp90 (and Hsp70 and the Hop/STIP1 adaptor) and promotes the interaction of client proteins, notably protein kinases, with the Hsp70/Hsp90 chaperone system, contributing to client folding and maturation. molecular_function: id: GO:0051087 label: protein-folding chaperone binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90. - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Self-associates. Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1. - description: Direct binding to the molecular chaperones Hsp90 and Hsp70, the structural basis for CDC37L1's co-chaperone adaptor activity. molecular_function: id: GO:0031072 label: heat shock protein binding locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/CDC37L1/CDC37L1-uniprot.txt supporting_text: Forms complexes with Hsp70 and Hsp90. - reference_id: file:human/CDC37L1/CDC37L1-goa.tsv supporting_text: GO:0005515 protein binding IPI WITH HSP90AA1 (P07900) and HSP90AB1 (P08238) proposed_new_terms: [] suggested_questions: - question: Does CDC37L1/Harc have a kinase-client specificity distinct from its paralog CDC37, or does it act redundantly within the Hsp90 kinase-maturation pathway? - question: 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? - question: 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? suggested_experiments: - description: 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. - description: 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. - description: 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.