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.