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.
| 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) |
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Download this section (compressed HTML)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?
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.
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