CLGN

UniProt ID: O14967
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

Calmegin (CLGN) is a testis-specific, type I single-pass integral membrane lectin-type molecular chaperone of the endoplasmic reticulum that is homologous to calnexin and belongs to the calreticulin/calnexin family. Its luminal domain contains a globular concanavalin A-like lectin fold and the extended proline-rich P domain characteristic of calnexin/calreticulin, and it binds calcium ions. Expressed during spermatogenesis in male germ cells, calmegin binds nascent polypeptides and assists the folding and assembly of a range of client proteins required for sperm function, most notably the ADAM-family sperm surface proteins fertilin (ADAM1/ADAM2) and ADAM3, whose maturation and heterodimerization depend on it. It forms a germ-cell ER chaperone complex with the testis-specific protein disulfide isomerase-like protein PDILT and also interacts with the peptidyl-prolyl isomerase cyclophilin B (PPIB), paralleling the calnexin/ERp57 system. Through chaperoning these clients, calmegin is essential for sperm adhesion to and penetration of the egg zona pellucida and for sperm migration from the uterus into the oviduct; loss of function causes male infertility in mice.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0006457 protein folding
IBA
GO_REF:0000033 		ACCEPT
Summary: Protein folding is a core biological process for calmegin, which functions as an ER molecular chaperone that binds nascent polypeptides during spermatogenesis.
Reason: Phylogenetic transfer within the calnexin/calreticulin family agrees with direct experimental evidence that calmegin binds nascent polypeptides and acts as a folding chaperone for spermatogenic client proteins.
Supporting Evidence:
PMID:9177349
calmegin binds to nascent polypeptides during spermatogenesis
file:human/CLGN/CLGN-uniprot.txt
Functions during spermatogenesis as a chaperone for a range of client proteins
GO:0036503 ERAD pathway
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: ERAD participation is a generic phylogenetic transfer from the calnexin/calreticulin family. Calmegin's documented role is the folding and assembly of spermatogenic clients (notably the ADAM proteins), not demonstrated involvement in ER-associated degradation.
Reason: No experimental evidence links calmegin to the ERAD pathway; the annotation is inherited from broadly conserved calnexin/calreticulin family members and over-extends calmegin's characterized function.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Functions during spermatogenesis as a chaperone for a range of client proteins
GO:0005509 calcium ion binding
IBA
GO_REF:0000033 		ACCEPT
Summary: Calmegin is a calcium-binding ER chaperone of the calnexin/calreticulin family; calcium ion binding is a core molecular function.
Reason: Calcium binding is conserved across the calnexin/calreticulin family and is supported by UniProt; the phylogenetic transfer is appropriate.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Binds calcium ions
GO:0005509 calcium ion binding
IEA
GO_REF:0000120 		ACCEPT
Summary: Calcium ion binding by InterPro/automated transfer, consistent with calmegin's membership in the calcium-binding calnexin/calreticulin family.
Reason: This IEA annotation agrees with the IBA and with UniProt; calcium binding is a conserved core function of the family.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Binds calcium ions
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Calmegin localizes to the endoplasmic reticulum. This is a less precise parent of the more accurate ER membrane location.
Reason: Correct but less specific than the endoplasmic reticulum membrane annotation; calmegin is a single-pass type I ER membrane protein, so the membrane term is preferred as the core localization.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Calmegin is a single-pass type I integral membrane protein of the endoplasmic reticulum membrane; this is the core subcellular localization.
Reason: The subcellular location mapping agrees with UniProt's annotation of calmegin as an ER membrane single-pass type I protein.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Endoplasmic reticulum membrane; Single-pass type I membrane protein
GO:0006457 protein folding
IEA
GO_REF:0000002 		ACCEPT
Summary: Protein folding inferred from the InterPro calreticulin/calnexin signature, consistent with calmegin's chaperone function.
Reason: Agrees with the experimentally supported IBA annotation; calmegin assists folding of nascent client proteins.
Supporting Evidence:
PMID:9177349
calmegin binds to nascent polypeptides during spermatogenesis
file:human/CLGN/CLGN-uniprot.txt
Functions during spermatogenesis as a chaperone for a range of client proteins
GO:0005635 nuclear envelope
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Nuclear envelope is an automated Ensembl transfer from the mouse ortholog. The nuclear envelope is continuous with the ER, so this is a low-value over-transfer rather than a distinct biological site for calmegin.
Reason: Calmegin is documented as an ER membrane protein; the nuclear envelope annotation likely reflects ER continuity with the outer nuclear membrane and adds no specific functional information.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Endoplasmic reticulum membrane; Single-pass type I membrane protein
GO:0044183 protein folding chaperone
IEA
GO_REF:0000107 		ACCEPT
Summary: Calmegin acts as a molecular chaperone that promotes folding of client proteins; protein folding chaperone is a core molecular function.
Reason: Supported by experimental evidence that calmegin binds nascent polypeptides and chaperones spermatogenic clients, and by its membership in the calnexin chaperone family.
Supporting Evidence:
PMID:9177349
calmegin functions as a chaperone for one or more sperm surface proteins that mediate the interactions between sperm and egg
file:human/CLGN/CLGN-uniprot.txt
Functions during spermatogenesis as a chaperone for a range of client proteins
GO:0005783 endoplasmic reticulum
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: Immunofluorescence (HPA) localizes calmegin to the endoplasmic reticulum, consistent with its role as an ER membrane chaperone. Less precise than the ER membrane term.
Reason: Directly observed ER localization is correct but less specific than the ER membrane annotation, which better reflects calmegin as a single-pass type I membrane protein.
Supporting Evidence:
file:human/CLGN/CLGN-uniprot.txt
Endoplasmic reticulum membrane
GO:0005783 endoplasmic reticulum
TAS
PMID:9177349
The putative chaperone calmegin is required for sperm fertil... 		KEEP AS NON CORE
Summary: Calmegin is described as a testis-specific ER protein homologous to calnexin; ER localization is well supported. Less precise than the ER membrane term.
Reason: Correct ER localization but less specific than the endoplasmic reticulum membrane annotation that captures calmegin's single-pass membrane topology.
Supporting Evidence:
PMID:9177349
Calmegin is a testis-specific ER protein that is homologous to calnexin
GO:0007338 single fertilization
TAS
PMID:9177349
The putative chaperone calmegin is required for sperm fertil... 		ACCEPT
Summary: Calmegin is required for sperm fertility; Clgn-null male mice are nearly sterile because sperm fail to adhere to the egg zona pellucida. Its role in fertilization is well supported, though it acts indirectly via chaperoning sperm surface client proteins.
Reason: Genetic disruption in mouse demonstrates an essential role in sperm-egg interaction and fertilization, supporting involvement in single fertilization.
Supporting Evidence:
PMID:9177349
Homozygous-null male mice are nearly sterile even though spermatogenesis is morphologically normal and mating is normal. In vitro, sperm from homozygous-null males do not adhere to the egg extracellular matrix (zona pellucida)

Core Functions

Calcium-binding, lectin-type ER membrane molecular chaperone (calnexin family) that binds nascent polypeptides and assists their folding and assembly in the endoplasmic reticulum of male germ cells.

Molecular Function:
protein folding chaperone
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • PMID:9177349
    calmegin binds to nascent polypeptides during spermatogenesis
  • file:human/CLGN/CLGN-uniprot.txt
    Functions during spermatogenesis as a chaperone for a range of client proteins

Chaperone-mediated maturation of sperm surface client proteins required for sperm to adhere to and penetrate the egg zona pellucida and to migrate into the oviduct, making calmegin essential for male fertility.

Directly Involved In:
single fertilization
Supporting Evidence:
  • PMID:9177349
    calmegin functions as a chaperone for one or more sperm surface proteins that mediate the interactions between sperm and egg
  • file:human/CLGN/CLGN-uniprot.txt
    a chaperone for a range of client proteins that are important for sperm adhesion onto the egg zona pellucida and for subsequent penetration of the zona pellucida

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:9177349
The putative chaperone calmegin is required for sperm fertility.
  • Calmegin is a testis-specific ER membrane protein homologous to calnexin that binds nascent polypeptides during spermatogenesis; Clgn-null male mice are nearly sterile because their sperm fail to adhere to the egg zona pellucida.
    "Calmegin is a testis-specific ER protein that is homologous to calnexin. Here we show that calmegin binds to nascent polypeptides during spermatogenesis... Homozygous-null male mice are nearly sterile even though spermatogenesis is morphologically normal and mating is normal. In vitro, sperm from homozygous-null males do not adhere to the egg extracellular matrix (zona pellucida)"
PMID:17507649
A developmentally regulated chaperone complex for the endoplasmic reticulum of male haploid germ cells.
  • Calmegin interacts with the testis-specific protein disulfide isomerase-like protein PDILT, forming a germ-cell ER chaperone complex analogous to the calnexin/ERp57 system.
PMID:9434179
Cloning and characterization of the human Calmegin gene encoding putative testis-specific chaperone.
  • Human calmegin is a putative testis-specific chaperone; expression is detected in testis.

Suggested Questions for Experts

Q: Does human calmegin chaperone the same ADAM-family clients (ADAM1/ADAM2/ADAM3) as mouse calmegin, given that human ADAM3 is a pseudogene?

Q: What is the full client repertoire of calmegin beyond the ADAM proteins, and how does it partition clients with ubiquitous calnexin in germ cells?

Suggested Experiments

Experiment: Affinity capture / proximity labeling (e.g. BioID) of calmegin in human or mouse spermatogenic cells to define its in vivo client interactome.

Experiment: Reconstitution assays testing whether calmegin, in complex with PDILT, supports oxidative folding of ADAM substrates analogous to the calnexin/ERp57 system.

Experiment: Lectin-binding assays to confirm whether calmegin retains the monoglucosylated N-glycan binding activity characteristic of calnexin/calreticulin lectin chaperones.

📚 Additional Documentation

Notes

(CLGN-notes.md)

CLGN (Calmegin) — Gene Review Notes

UniProt: O14967 (CLGN_HUMAN), 610 aa, gene HGNC:2060, chromosome 4. Precursor with N-terminal signal peptide (1–19); single-pass type I ER membrane protein (lumenal 20–471, TM 472–492, cytoplasmic 493–610).

Identity and family

  • Calmegin is a testis-specific ER membrane molecular chaperone homologous to calnexin. UniProt SIMILARITY: "Belongs to the calreticulin family" [file:human/CLGN/CLGN-uniprot.txt]. InterPro/Pfam signatures: IPR001580 (Calreticulin/calnexin), Calreticulin Pfam PF00262, ConA-like lectin domain (SSF49899), and the calnexin/calreticulin P-domain (Gene3D 2.10.250.10, SSF63887). PANTHER subfamily PTHR11073:SF7 = CALMEGIN; parent PTHR11073 = CALRETICULIN AND CALNEXIN.
  • Like calnexin, it is a calcium-binding, lectin-type ER chaperone. KW: Calcium, Chaperone, Endoplasmic reticulum, Membrane, Signal, Transmembrane.

Function (UniProt FUNCTION)

"Functions during spermatogenesis as a chaperone for a range of client proteins that are important for sperm adhesion onto the egg zona pellucida and for subsequent penetration of the zona pellucida. Required for normal sperm migration from the uterus into the oviduct. Required for normal male fertility. Binds calcium ions (By similarity)." [file:human/CLGN/CLGN-uniprot.txt]

Key experimental evidence

  • PMID:9177349 — Mouse Clgn knockout; the foundational functional paper. Establishes ER localization, chaperone binding to nascent polypeptides, and essential role in sperm–zona adhesion / fertilization. This is the basis for the TAS annotations to ER (GO:0005783) and single fertilization (GO:0007338).
  • Mouse work (Ikawa et al.) showed calmegin is required for maturation/heterodimerization of sperm ADAM proteins fertilin (ADAM1/ADAM2) and ADAM3; loss disrupts sperm migration into the oviduct and zona binding (biological hint, consistent with UniProt FUNCTION). UniProt SUBUNIT: "Interacts with ADAM2 (By similarity)."

Interactions

  • UniProt SUBUNIT: "Interacts with PPIB. Interacts with ADAM2 (By similarity). Interacts with PDILT." [file:human/CLGN/CLGN-uniprot.txt]
  • PMID:17507649 — Calmegin interacts with PDILT (testis-specific protein disulfide isomerase-like protein), forming a germ-cell ER chaperone complex (analogous to the calnexin–ERp57 complex). Supports ER-membrane chaperone function.
  • Region 317–350 = interaction with PPIB (peptidyl-prolyl cis-trans isomerase B); Region 521–610 disordered cytoplasmic tail.

Localization

  • ER membrane, single-pass type I (UniProt SUBCELLULAR LOCATION). HPA IDA also localizes to ER (GO:0005783, GO_REF:0000052). TAS ER from PMID:9177349.
  • Nuclear envelope (GO:0005635) annotation is IEA from mouse ortholog (Ensembl GO_REF:0000107); the NE is continuous with the ER, so this is a low-value over-transfer, not a distinct biological site.

Tissue specificity

  • Testis-specific (at protein level) [PMID:9434179 cloning paper; UniProt TISSUE SPECIFICITY ECO:0000269|PubMed:9434179]. HPA: tissue enhanced (heart muscle, testis).

Annotation assessment summary

  • Core MF: lectin/calcium-binding ER molecular chaperone (calnexin family). protein folding chaperone (GO:0044183), unfolded protein binding (GO:0051082), calcium ion binding (GO:0005509) — all supported.
  • Core CC: ER membrane (GO:0005789) / ER (GO:0005783).
  • Core BP: protein folding (GO:0006457) during spermatogenesis; role in fertilization/sperm–zona binding (GO:0007338 single fertilization; GO:0007339 binding of sperm to zona pellucida).
  • ERAD pathway (GO:0036503) IBA: generic transfer from calnexin/calreticulin family; calmegin's documented role is folding/assembly of spermatogenic clients (notably ADAMs), not demonstrated ERAD. Over-annotated phylogenetic transfer.
  • Nuclear envelope (GO:0005635) IEA: low-value over-transfer (NE continuous with ER). Mark over-annotated / keep non-core.

Pn Notes

(CLGN-pn-notes.md)

CLGN PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O14967
  • 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: Calmegin (CLGN) is a testis-specific, type I single-pass integral membrane lectin-type molecular chaperone of the endoplasmic reticulum that is homologous to calnexin and belongs to the calreticulin/calnexin family. Its luminal domain contains a globular concanavalin A-like lectin fold and the extended proline-rich P domain characteristic of calnexin/calreticulin, and it binds calcium ions. Expressed during spermatogenesis in male germ cells, calmegin binds nascent polypeptides and assists the folding and assembly of a range of client proteins required for sperm function, most notably the ADAM-family sperm surface proteins fertilin (ADAM1/ADAM2) and ADAM3, whose maturation and heterodimerization depend on it. It forms a germ-cell ER chaperone complex with the testis-specific protein disulfide isomerase-like protein PDILT and also interacts with the peptidyl-prolyl isomerase cyclophilin B (PPIB), paralleling the calnexin/ERp57 system. Through chaperoning these clients, calmegin is essential for sperm adhesion to and penetration of the egg zona pellucida and for sperm migration from the uterus into the oviduct; loss of function causes male infertility in mice.
  • Existing/core annotation action counts: ACCEPT: 7; KEEP_AS_NON_CORE: 3; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

  • Consistency: Mostly consistent on identity (testis-specific calnexin-family lectin-type ER membrane chaperone; clients = ADAM1/2/ADAM3; essential for sperm-zona binding/fertility) across notes, YAML, and PN. The friction is the projected GO term: the PN node projects GO:0006487 (the biosynthetic process that adds N-glycans), but CLGN is a lectin chaperone that binds monoglucosylated N-glycans on clients — it does not catalyze glycan transfer. The review correctly annotates GO:0044183 protein folding chaperone / GO:0006457 protein folding, not glycosylation.
  • PN story / NEW pressure: PN's "N-glycosylation system" framing over-reaches when projected as GO:0006487 for a lectin chaperone. CLGN's real, review-captured roles (folding chaperone, single fertilization GO:0007338) are already in GOA/review. GO:0006487 is verified real but is the WRONG process for this gene's mechanism → over-reaches; do not ADD to the gene.
  • Evidence alignment: PN listed no reference titles for this row. Review anchors on PMID:9177349 (knockout/zona-adhesion), PMID:17507649 (PDILT complex), PMID:9434179 (cloning). No conflict; the divergence is term choice, not evidence.
  • Verdict: Identity consistent, but PN GO:0006487 projection over-reaches for a lectin chaperone (binds, not synthesizes, N-glycans); should not propagate to CLGN.

Full Consistency Review

  • UniProt: O14967 · batch: proteostasis-batch-2026-06-07 · review status: COMPLETE
  • PN placement: ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone ; PN-node mapping: leaf [type] Lectin chaperone no_mapping; [group] N-glycosylation system → mapped GO:0006487 protein N-linked glycosylation (new_to_goa); class/branch unmapped.
  • Consistency: Mostly consistent on identity (testis-specific calnexin-family lectin-type ER membrane chaperone; clients = ADAM1/2/ADAM3; essential for sperm-zona binding/fertility) across notes, YAML, and PN. The friction is the projected GO term: the PN node projects GO:0006487 (the biosynthetic process that adds N-glycans), but CLGN is a lectin chaperone that binds monoglucosylated N-glycans on clients — it does not catalyze glycan transfer. The review correctly annotates GO:0044183 protein folding chaperone / GO:0006457 protein folding, not glycosylation.
  • PN story / NEW pressure: PN's "N-glycosylation system" framing over-reaches when projected as GO:0006487 for a lectin chaperone. CLGN's real, review-captured roles (folding chaperone, single fertilization GO:0007338) are already in GOA/review. GO:0006487 is verified real but is the WRONG process for this gene's mechanism → over-reaches; do not ADD to the gene.
  • Mapping strategy: The [group] projection is the problem. GO:0006487 is broader/orthogonal to what lectin chaperones do; it is analogous to the TOMM20/HSPA8/RAB7A "broader, rejected" precedent — the node groups the N-glycosylation machinery but its members (OST subunits vs lectin chaperones) do not share GO:0006487. Recommend the group either map to a glycoprotein-QC/folding term (e.g. a chaperone-mediated folding concept) or leave lectin-chaperone members unmapped at this node, so GO:0006487 is not propagated to CLGN.
  • Evidence alignment: PN listed no reference titles for this row. Review anchors on PMID:9177349 (knockout/zona-adhesion), PMID:17507649 (PDILT complex), PMID:9434179 (cloning). No conflict; the divergence is term choice, not evidence.
  • Verdict: Identity consistent, but PN GO:0006487 projection over-reaches for a lectin chaperone (binds, not synthesizes, N-glycans); should not propagate to CLGN.

Recommended edits: [MAP] Do not propagate GO:0006487 from N-glycosylation system to lectin-chaperone members (CLGN); remap the group to a folding/glycoprotein-QC term or leave lectin chaperones unmapped. [YAML] No glycosylation annotation should be added to CLGN.

PN Dossier Context

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

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | Lectin chaperone

  • UniProt: O14967
  • In branches: ER
  • PN-node mapping records (path + ancestors):
    • [type] ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [group] ER proteostasis|Glycoproteostasis|N-glycosylation system
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006487 protein N-linked glycosylation]
      rationale: This PN group captures the ER N-glycosylation machinery that installs and processes N-linked glycans during proteostasis. GO protein N-linked glycosylation is the best current propagation target in the local cache.
    • [class] ER proteostasis|Glycoproteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER 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:0006487 protein N-linked glycosylation | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Glycoproteostasis|N-glycosylation system

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.

📄 View Raw YAML

 
id: O14967
gene_symbol: CLGN
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Calmegin (CLGN) is a testis-specific, type I single-pass integral membrane
  lectin-type molecular chaperone of the endoplasmic reticulum that is homologous to
  calnexin and belongs to the calreticulin/calnexin family. Its luminal domain contains
  a globular concanavalin A-like lectin fold and the extended proline-rich P domain
  characteristic of calnexin/calreticulin, and it binds calcium ions. Expressed during
  spermatogenesis in male germ cells, calmegin binds nascent polypeptides and assists
  the folding and assembly of a range of client proteins required for sperm function,
  most notably the ADAM-family sperm surface proteins fertilin (ADAM1/ADAM2) and ADAM3,
  whose maturation and heterodimerization depend on it. It forms a germ-cell ER chaperone
  complex with the testis-specific protein disulfide isomerase-like protein PDILT and
  also interacts with the peptidyl-prolyl isomerase cyclophilin B (PPIB), paralleling
  the calnexin/ERp57 system. Through chaperoning these clients, calmegin is essential
  for sperm adhesion to and penetration of the egg zona pellucida and for sperm migration
  from the uterus into the oviduct; loss of function causes male infertility in mice.
alternative_products:
- name: '1'
  id: O14967-1
- name: '2'
  id: O14967-2
  sequence_note: VSP_055517, VSP_055518
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Protein folding is a core biological process for calmegin, which functions
      as an ER molecular chaperone that binds nascent polypeptides during spermatogenesis.
    action: ACCEPT
    reason: Phylogenetic transfer within the calnexin/calreticulin family agrees with
      direct experimental evidence that calmegin binds nascent polypeptides and acts
      as a folding chaperone for spermatogenic client proteins.
    supported_by:
    - reference_id: PMID:9177349
      supporting_text: calmegin binds to nascent polypeptides during spermatogenesis
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Functions during spermatogenesis as a chaperone for a range
        of client proteins
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: ERAD participation is a generic phylogenetic transfer from the calnexin/calreticulin
      family. Calmegin's documented role is the folding and assembly of spermatogenic
      clients (notably the ADAM proteins), not demonstrated involvement in ER-associated
      degradation.
    action: MARK_AS_OVER_ANNOTATED
    reason: No experimental evidence links calmegin to the ERAD pathway; the annotation
      is inherited from broadly conserved calnexin/calreticulin family members and
      over-extends calmegin's characterized function.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Functions during spermatogenesis as a chaperone for a range
        of client proteins
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Calmegin is a calcium-binding ER chaperone of the calnexin/calreticulin
      family; calcium ion binding is a core molecular function.
    action: ACCEPT
    reason: Calcium binding is conserved across the calnexin/calreticulin family and
      is supported by UniProt; the phylogenetic transfer is appropriate.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Binds calcium ions
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Calcium ion binding by InterPro/automated transfer, consistent with calmegin's
      membership in the calcium-binding calnexin/calreticulin family.
    action: ACCEPT
    reason: This IEA annotation agrees with the IBA and with UniProt; calcium binding
      is a conserved core function of the family.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Binds calcium ions
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Calmegin localizes to the endoplasmic reticulum. This is a less precise
      parent of the more accurate ER membrane location.
    action: KEEP_AS_NON_CORE
    reason: Correct but less specific than the endoplasmic reticulum membrane annotation;
      calmegin is a single-pass type I ER membrane protein, so the membrane term is
      preferred as the core localization.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Calmegin is a single-pass type I integral membrane protein of the endoplasmic
      reticulum membrane; this is the core subcellular localization.
    action: ACCEPT
    reason: The subcellular location mapping agrees with UniProt's annotation of calmegin
      as an ER membrane single-pass type I protein.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane; Single-pass type I membrane
        protein
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Protein folding inferred from the InterPro calreticulin/calnexin signature,
      consistent with calmegin's chaperone function.
    action: ACCEPT
    reason: Agrees with the experimentally supported IBA annotation; calmegin assists
      folding of nascent client proteins.
    supported_by:
    - reference_id: PMID:9177349
      supporting_text: calmegin binds to nascent polypeptides during spermatogenesis
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Functions during spermatogenesis as a chaperone for a range
        of client proteins
- term:
    id: GO:0005635
    label: nuclear envelope
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Nuclear envelope is an automated Ensembl transfer from the mouse ortholog.
      The nuclear envelope is continuous with the ER, so this is a low-value over-transfer
      rather than a distinct biological site for calmegin.
    action: MARK_AS_OVER_ANNOTATED
    reason: Calmegin is documented as an ER membrane protein; the nuclear envelope
      annotation likely reflects ER continuity with the outer nuclear membrane and
      adds no specific functional information.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane; Single-pass type I membrane
        protein
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Calmegin acts as a molecular chaperone that promotes folding of client
      proteins; protein folding chaperone is a core molecular function.
    action: ACCEPT
    reason: Supported by experimental evidence that calmegin binds nascent polypeptides
      and chaperones spermatogenic clients, and by its membership in the calnexin chaperone
      family.
    supported_by:
    - reference_id: PMID:9177349
      supporting_text: calmegin functions as a chaperone for one or more sperm surface
        proteins that mediate the interactions between sperm and egg
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Functions during spermatogenesis as a chaperone for a range
        of client proteins
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence (HPA) localizes calmegin to the endoplasmic reticulum,
      consistent with its role as an ER membrane chaperone. Less precise than the ER
      membrane term.
    action: KEEP_AS_NON_CORE
    reason: Directly observed ER localization is correct but less specific than the
      ER membrane annotation, which better reflects calmegin as a single-pass type
      I membrane protein.
    supported_by:
    - reference_id: file:human/CLGN/CLGN-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:9177349
  qualifier: located_in
  review:
    summary: Calmegin is described as a testis-specific ER protein homologous to calnexin;
      ER localization is well supported. Less precise than the ER membrane term.
    action: KEEP_AS_NON_CORE
    reason: Correct ER localization but less specific than the endoplasmic reticulum
      membrane annotation that captures calmegin's single-pass membrane topology.
    supported_by:
    - reference_id: PMID:9177349
      supporting_text: Calmegin is a testis-specific ER protein that is homologous
        to calnexin
- term:
    id: GO:0007338
    label: single fertilization
  evidence_type: TAS
  original_reference_id: PMID:9177349
  qualifier: involved_in
  review:
    summary: Calmegin is required for sperm fertility; Clgn-null male mice are nearly
      sterile because sperm fail to adhere to the egg zona pellucida. Its role in fertilization
      is well supported, though it acts indirectly via chaperoning sperm surface client
      proteins.
    action: ACCEPT
    reason: Genetic disruption in mouse demonstrates an essential role in sperm-egg
      interaction and fertilization, supporting involvement in single fertilization.
    supported_by:
    - reference_id: PMID:9177349
      supporting_text: Homozygous-null male mice are nearly sterile even though spermatogenesis
        is morphologically normal and mating is normal. In vitro, sperm from homozygous-null
        males do not adhere to the egg extracellular matrix (zona pellucida)
core_functions:
- description: Calcium-binding, lectin-type ER membrane molecular chaperone (calnexin
    family) that binds nascent polypeptides and assists their folding and assembly
    in the endoplasmic reticulum of male germ cells.
  supported_by:
  - reference_id: PMID:9177349
    supporting_text: calmegin binds to nascent polypeptides during spermatogenesis
  - reference_id: file:human/CLGN/CLGN-uniprot.txt
    supporting_text: Functions during spermatogenesis as a chaperone for a range of
      client proteins
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: Chaperone-mediated maturation of sperm surface client proteins required
    for sperm to adhere to and penetrate the egg zona pellucida and to migrate into
    the oviduct, making calmegin essential for male fertility.
  supported_by:
  - reference_id: PMID:9177349
    supporting_text: calmegin functions as a chaperone for one or more sperm surface
      proteins that mediate the interactions between sperm and egg
  - reference_id: file:human/CLGN/CLGN-uniprot.txt
    supporting_text: a chaperone for a range of client proteins that are important
      for sperm adhesion onto the egg zona pellucida and for subsequent penetration
      of the zona pellucida
  directly_involved_in:
  - id: GO:0007338
    label: single fertilization
proposed_new_terms: []
suggested_questions:
- question: Does human calmegin chaperone the same ADAM-family clients (ADAM1/ADAM2/ADAM3) as mouse calmegin, given that human ADAM3 is a pseudogene?
- question: What is the full client repertoire of calmegin beyond the ADAM proteins, and how does it partition clients with ubiquitous calnexin in germ cells?
suggested_experiments:
- description: Affinity capture / proximity labeling (e.g. BioID) of calmegin in human or mouse spermatogenic cells to define its in vivo client interactome.
- description: Reconstitution assays testing whether calmegin, in complex with PDILT, supports oxidative folding of ADAM substrates analogous to the calnexin/ERp57 system.
- description: Lectin-binding assays to confirm whether calmegin retains the monoglucosylated N-glycan binding activity characteristic of calnexin/calreticulin lectin chaperones.
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: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: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9177349
  title: The putative chaperone calmegin is required for sperm fertility.
  findings:
  - statement: Calmegin is a testis-specific ER membrane protein homologous to calnexin
      that binds nascent polypeptides during spermatogenesis; Clgn-null male mice are
      nearly sterile because their sperm fail to adhere to the egg zona pellucida.
    supporting_text: Calmegin is a testis-specific ER protein that is homologous to
      calnexin. Here we show that calmegin binds to nascent polypeptides during spermatogenesis...
      Homozygous-null male mice are nearly sterile even though spermatogenesis is morphologically
      normal and mating is normal. In vitro, sperm from homozygous-null males do not
      adhere to the egg extracellular matrix (zona pellucida)
- id: PMID:17507649
  title: A developmentally regulated chaperone complex for the endoplasmic reticulum
    of male haploid germ cells.
  findings:
  - statement: Calmegin interacts with the testis-specific protein disulfide isomerase-like
      protein PDILT, forming a germ-cell ER chaperone complex analogous to the calnexin/ERp57
      system.
- id: PMID:9434179
  title: Cloning and characterization of the human Calmegin gene encoding putative
    testis-specific chaperone.
  findings:
  - statement: Human calmegin is a putative testis-specific chaperone; expression is
      detected in testis.