CDC37L1

UniProt ID: Q7L3B6
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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 Review

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

Core Functions

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:
protein-folding chaperone binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/CDC37L1/CDC37L1-uniprot.txt
    Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90.
  • file:human/CDC37L1/CDC37L1-uniprot.txt
    Self-associates. Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1.

Direct binding to the molecular chaperones Hsp90 and Hsp70, the structural basis for CDC37L1's co-chaperone adaptor activity.

Molecular Function:
heat shock protein binding
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/CDC37L1/CDC37L1-uniprot.txt
    Forms complexes with Hsp70 and Hsp90.
  • file:human/CDC37L1/CDC37L1-goa.tsv
    GO:0005515 protein binding IPI WITH HSP90AA1 (P07900) and HSP90AB1 (P08238)

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:21988832
Toward an understanding of the protein interaction network of the human liver.
  • High-throughput liver interactome screen capturing a CDC37L1-HSP90AB1 interaction.
PMID:25036637
A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  • 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.
PMID:25416956
A proteome-scale map of the human interactome network.
  • Yeast two-hybrid human interactome map capturing a CDC37L1-HSP90AB1 interaction.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  • Neurodegeneration-focused interactome screen capturing a CDC37L1-BRK1 interaction.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  • BioPlex affinity-purification interactome capturing CDC37L1 interactions with HSP90AA1 and HSP90AB1.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
  • Multimodal cell-maps interactome capturing a CDC37L1-HSP90AB1 interaction.
Reactome:R-HSA-481009
Exocytosis of platelet dense granule content
file:human/CDC37L1/CDC37L1-uniprot.txt
UniProt entry Q7L3B6 (CD37L_HUMAN), Hsp90 co-chaperone Cdc37-like 1
  • 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.

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(CDC37L1-notes.md)

CDC37L1 (Hsp90 co-chaperone Cdc37-like 1, "Harc") review notes

UniProt: Q7L3B6 (CD37L_HUMAN). Gene symbol CDC37L1; synonyms CDC37B, HARC (Hsp90-Associating Relative of Cdc37). 337 aa. HGNC:17179. Chromosome 9.

Identity and family

  • RecName: "Hsp90 co-chaperone Cdc37-like 1"; AltName "Hsp90-associating relative of Cdc37" [file:human/CDC37L1/CDC37L1-uniprot.txt].
  • Belongs to the CDC37 family (UniProt SIMILARITY; SUPFAM SSF101391 "Hsp90 co-chaperone CDC37"; Pfam PF08565 CDC37_M; InterPro IPR004918 Cdc37, IPR013874 Cdc37_Hsp90-bd; PANTHER PTHR12800:SF2 "HSP90 CO-CHAPERONE CDC37-LIKE 1") [file:human/CDC37L1/CDC37L1-uniprot.txt].
  • Paralog of CDC37, the canonical kinase-specific Hsp90 co-chaperone.

Function (UniProt)

  • FUNCTION: "Co-chaperone that binds to numerous proteins and promotes their interaction with Hsp70 and Hsp90." (ECO:0000250, by similarity) [file:human/CDC37L1/CDC37L1-uniprot.txt].
  • SUBUNIT: "Self-associates. Forms complexes with Hsp70 and Hsp90. Interacts with CDC37, FKBP4, PPID and STIP1." (ECO:0000269|PubMed:11413142, PubMed:15850399, PubMed:18052042) [file:human/CDC37L1/CDC37L1-uniprot.txt].
  • INTERACTION (IntAct): binds HSP90AA1 (P07900), HSP90AB1 (P08238, Q6PK50), STIP1 (P31948), BRK1 (Q8WUW1) [file:human/CDC37L1/CDC37L1-uniprot.txt].

Primary literature (in UniProt, not cached locally)

  • PMID:11413142 (Scholz et al., 2001, J Biol Chem): original identification/characterization of Harc; interaction with FKBP4, HSP70, HSP90, PPID and STIP1; subcellular location (cytoplasm); tissue specificity; phosphorylation. Defines Harc as a novel Hsp90-associating relative of Cdc37.
  • PMID:15850399 (Roiniotis et al., 2005, Biochemistry): "Domain-mediated dimerization of the Hsp90 cochaperones Harc and Cdc37." Self-association and interaction with CDC37 and HSP90.
  • PMID:18052042 (Cartledge et al., 2007, Biochemistry): C-terminal domain of Harc required for binding HSP70 and Hop (STIP1) and response to heat shock.

Domain architecture (UniProt feature table) [file:human/CDC37L1/CDC37L1-uniprot.txt]

  • REGION 2..171 Self-association.
  • REGION 147..277 Self-association and interaction with Hsp90.
  • REGION 267..337 Interaction with Hsp70.
  • REGION 278..337 Required for interaction with STIP1 (Hop).
  • COILED 84..122.
  • Phosphoserine at S32 (PMID:18669648, PMID:19690332) and S88 (PMID:23186163) — large-scale phosphoproteomics; mitotic / TCR signaling contexts.

Subcellular location and tissue

  • Cytoplasm (PubMed:11413142); IDA cytosol (HPA, GO_REF:0000052) [file:human/CDC37L1/CDC37L1-goa.tsv].
  • Tissue: brain, heart, kidney, liver, placenta, skeletal muscle (PubMed:11413142); HPA "Tissue enhanced (skeletal)".

GOA annotations reviewed [file:human/CDC37L1/CDC37L1-goa.tsv]

  • IBA (GO_REF:0000033, PANTHER PTN000980613): cytoplasm GO:0005737; protein folding GO:0006457; heat shock protein binding GO:0031072; protein stabilization GO:0050821; protein-folding chaperone binding GO:0051087. (UniProt DR also lists IBA GO:0051082 unfolded protein binding, but this is not in the GOA TSV.)
  • IEA cytoplasm GO:0005737 (GO_REF:0000120).
  • IDA cytosol GO:0005829 (HPA, GO_REF:0000052).
  • IPI protein binding GO:0005515 from high-throughput interactome/proteomics screens:
  • PMID:21988832 (human liver interactome) WITH HSP90AB1 (P08238).
  • PMID:25036637 (Taipale chaperone interaction network) WITH HSP90AA1 (P07900), HSP90AB1 (P08238, Q6PK50), STIP1 (P31948). This is the most biologically relevant: it maps CDC37L1 into the Hsp90 co-chaperone module of the chaperome.
  • PMID:25416956 (Rolland human interactome Y2H) WITH HSP90AB1 (P08238).
  • PMID:32814053 (Haenig neurodegeneration interactome) WITH BRK1 (Q8WUW1).
  • PMID:33961781 (Huttlin BioPlex) WITH HSP90AA1 (P07900), HSP90AB1 (P08238).
  • PMID:40205054 (Schaffer multimodal cell maps) WITH HSP90AB1 (P08238).
    These cached papers are genome-scale screens; none discuss CDC37L1 mechanistically in body text, but the WITH partners (HSP90AA1/AB1, STIP1) are consistent with the co-chaperone role.
  • TAS (Reactome:R-HSA-481009 "Exocytosis of platelet dense granule content"): extracellular region GO:0005576; platelet dense granule lumen GO:0031089. CDC37L1 was detected in platelet releasate / dense granule proteomics; this is a localization annotation from platelet biology, not its core chaperone function. Keep as non-core (curated TAS, plausible localization) rather than removing.

Interpretation / review decisions

  • Core function: HSP90/HSP70 co-chaperone — adaptor that binds Hsp90 (and Hsp70/Hop) and promotes client (notably protein kinase) folding/maturation, paralogous to CDC37.
  • Specific binding terms supported: heat shock protein binding (GO:0031072), protein-folding chaperone binding (GO:0051087), Hsp90 protein binding (GO:0051879). The bare "protein binding" GO:0005515 IPI annotations are uninformative; where the WITH partner is HSP90 these are better captured by GO:0051879 Hsp90 protein binding, but per curation guidelines the redundant bare-protein-binding rows are marked over-annotated (the specific HSP90 binding is already covered by the IBA heat shock protein binding term).
  • Note: GO:0003767 "co-chaperone activity", GO:0061077 "chaperone-mediated protein folding", and GO:0051085 are OBSOLETE — do not use.
  • Annotations such as protein folding (GO:0006457) and protein stabilization (GO:0050821) are reasonable BP outcomes of the co-chaperone role (kept as non-core since CDC37L1's direct molecular role is co-chaperone binding/adaptor, with folding/stabilization being downstream of the Hsp90 machine).

Pn Notes

(CDC37L1-pn-notes.md)

CDC37L1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q7L3B6
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • 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/core annotation action counts: ACCEPT: 5; KEEP_AS_NON_CORE: 4; MARK_AS_OVER_ANNOTATED: 1; MODIFY: 5

PN Consistency Summary

  • Consistency: Consistent. Notes, YAML, and PN all frame CDC37L1 (Harc) as a cytoplasmic HSP90/HSP70 co-chaperone (CDC37 paralog). GO:0051879 verified real. The review's repeated MODIFY of bare GO:0005515 IPI rows (WITH HSP90AA1/AB1) → GO:0051879 directly matches the PN projection. No contradictions.
  • PN story / NEW pressure: PN asserts Hsp90 binding (GO:0051879), which is not present verbatim in GOA (GOA has GO:0031072 heat shock protein binding IBA + bare GO:0005515 IPI to HSP90AA1/AB1). The review already proposes GO:0051879 via MODIFY of the IPI rows, so the PN story is captured by the review and defensibly more specific than the existing heat-shock-protein-binding parent. ADD is effectively already in the review; no over-reach.
  • Evidence alignment: PN listed no reference titles for this row. Review evidence is genome-scale interactome screens (PMID:25036637 Taipale chaperome map is the most informative; PMID:21988832/25416956/33961781/40205054). WITH partners (HSP90AA1 P07900, HSP90AB1 P08238, STIP1 P31948) underpin the GO:0051879 call. No divergence.
  • Verdict: Consistent; PN's GO:0051879 is defensible and already operationalized in the review (MODIFY of IPI rows). No new pressure beyond the review.

Full Consistency Review

  • UniProt: Q7L3B6 · batch: proteostasis-batch-2026-06-07 · review status: COMPLETE
  • PN placement: Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|no characteristic domain ; PN-node mapping: leaf/group/class/branch all no_mapping; [type] HSP90 cochaperone → mapped GO:0051879 Hsp90 protein binding (more_specific_than_existing_goa).
  • Consistency: Consistent. Notes, YAML, and PN all frame CDC37L1 (Harc) as a cytoplasmic HSP90/HSP70 co-chaperone (CDC37 paralog). GO:0051879 verified real. The review's repeated MODIFY of bare GO:0005515 IPI rows (WITH HSP90AA1/AB1) → GO:0051879 directly matches the PN projection. No contradictions.
  • PN story / NEW pressure: PN asserts Hsp90 binding (GO:0051879), which is not present verbatim in GOA (GOA has GO:0031072 heat shock protein binding IBA + bare GO:0005515 IPI to HSP90AA1/AB1). The review already proposes GO:0051879 via MODIFY of the IPI rows, so the PN story is captured by the review and defensibly more specific than the existing heat-shock-protein-binding parent. ADD is effectively already in the review; no over-reach.
  • Mapping strategy: No change. PN maps conservatively at the [type] altitude (cochaperone), with the family/system containers left unmapped — appropriate given CDC37 vs CDC37L1 client divergence. more_specific_than_existing_goa is accurate (GO:0051879 is a child concept of the generic heat shock / protein binding annotations).
  • Evidence alignment: PN listed no reference titles for this row. Review evidence is genome-scale interactome screens (PMID:25036637 Taipale chaperome map is the most informative; PMID:21988832/25416956/33961781/40205054). WITH partners (HSP90AA1 P07900, HSP90AB1 P08238, STIP1 P31948) underpin the GO:0051879 call. No divergence.
  • Verdict: Consistent; PN's GO:0051879 is defensible and already operationalized in the review (MODIFY of IPI rows). No new pressure beyond the review.

Recommended edits: None required. (Review already maps the HSP90-binding IPI evidence to GO:0051879, aligning with the PN node.)

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07
  • review_yaml: genes/human/CDC37L1/CDC37L1-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Cytonuclear proteostasis | Chaperone | HSP90 system | HSP90 cochaperone | no characteristic domain

  • UniProt: Q7L3B6
  • In branches: CY
  • PN-node mapping records (path + ancestors):
    • [subtype] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone|no characteristic domain
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower taxonomy bucket that is already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
    • [type] Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0051879 Hsp90 protein binding]
      rationale: This PN type groups HSP90 cochaperones. Hsp90 protein binding is the most defensible shared GO molecular-function target for propagation.
    • [group] Cytonuclear proteostasis|Chaperone|HSP90 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0051879 Hsp90 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP90 system|HSP90 cochaperone

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

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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.