CCDC47 (also called calumin) is a widely conserved, single-pass type I endoplasmic reticulum membrane protein with a small cytosolic domain, a single transmembrane helix, and a large luminal domain ending in a disordered, basic, coiled-coil region. It is the scaffold subunit of the PAT (protein associated with the ER translocon) complex, an obligate heterodimer with WDR83OS/Asterix. The PAT complex is one of three accessory subcomplexes (GEL, BOS, PAT) of the ribosome-associated multi-pass translocon (MPT) that assembles around the Sec61 channel during synthesis of multi-pass membrane proteins. Within this assembly CCDC47 occludes the lateral gate of Sec61 and stabilizes Asterix, which directly engages and shields hydrophilic transmembrane segments of nascent multi-pass clients until they fold, thereby promoting the biogenesis of GPCRs, channels, transporters and other polytopic membrane proteins. CCDC47 binds Ca2+ with low affinity and high capacity and contributes to ER calcium storage and signaling, and it has been linked to ER-associated degradation (ERAD) and to maintenance of ER organization during embryogenesis. Biallelic loss-of-function variants cause an autosomal recessive trichohepatoneurodevelopmental syndrome (woolly hair, liver dysfunction, dysmorphic features, hypotonia, developmental delay).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER localization is well supported and is the compartment where CCDC47 performs its core membrane-biogenesis scaffold function. Reason: CCDC47 is an ER-resident membrane protein, directly demonstrated by multiple experimental studies; ER residence is required for its role in the multi-pass translocon. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane PMID:32814900 CCDC47 is an ER-resident single-pass membrane protein with a well-conserved cytosolic domain |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CCDC47/calumin binds calcium with low affinity and high capacity, consistent with an ER calcium-buffering property, but this is secondary to its membrane-biogenesis role. Reason: Calcium binding is a genuine biochemical property supporting ER calcium storage, but the central, conserved function of CCDC47 is as the PAT/MPT scaffold; retain as non-core. Supporting Evidence: PMID:30401460 CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated transfer of calcium ion binding agrees with experimental low-affinity, high-capacity Ca2+ binding by CCDC47/calumin. Reason: Consistent with experimental evidence; retained as non-core relative to the membrane-biogenesis scaffold function. Supporting Evidence: PMID:30401460 CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Automated ER localization is consistent with direct experimental evidence. Reason: ER residence is well established and is core to CCDC47 function. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER membrane localization is the precise, well-supported compartment for this single-pass type I membrane protein. Reason: Direct experimental and structural evidence place CCDC47 in the ER membrane as part of the translocon; this is the correct specific localization term. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane PMID:32814900 CCDC47 is an ER-resident single-pass membrane protein with a well-conserved cytosolic domain |
| GO:0006457 protein folding | IEA GO_REF:0000108 | MODIFY | Summary: Generic protein folding understates CCDC47's specific role; the PAT/MPT function is membrane protein biogenesis/insertion, best captured by the specific multi-pass insertion term. Reason: CCDC47 acts as an intramembrane chaperone in multi-pass membrane protein biogenesis rather than in generic (soluble) protein folding; replace with the specific process term. Proposed replacements: multi-pass transmembrane protein insertion into ER membrane Supporting Evidence: PMID:32814900 Thus, the PAT complex is an intramembrane chaperone that protects TMDs during assembly to minimize misfolding of multi-spanning membrane proteins and maintain cellular protein homeostasis. |
| GO:0030867 rough endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Rough ER membrane is consistent with CCDC47 being a ribosome-associated translocon component. Reason: CCDC47 is part of a ribosome-bound (rough ER) translocon assembly; the rough ER membrane localization is appropriate. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt Rough endoplasmic reticulum membrane |
| GO:0032469 endoplasmic reticulum calcium ion homeostasis | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ER calcium homeostasis is supported by patient-cell data showing reduced ER calcium stores, but is secondary to the biogenesis scaffold function. Reason: Loss-of-function patient cells show decreased ER Ca2+ storage and impaired Ca2+ signaling, supporting a role in ER calcium homeostasis; retain as a non-core contextual function. Supporting Evidence: PMID:30401460 In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from an innate-immunity interaction network is uninformative for CCDC47 function. Reason: Bare protein binding from a high-throughput interactome does not capture a physiologically interpretable CCDC47 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from a neurodegenerative-disease interactome map is uninformative. Reason: High-throughput protein binding does not identify a specific CCDC47 molecular function. |
| GO:0005515 protein binding | IPI PMID:32814900 An intramembrane chaperone complex facilitates membrane prot... | MARK AS OVER ANNOTATED | Summary: The meaningful interaction underlying this annotation is the obligate CCDC47-Asterix (WDR83OS) PAT complex, which is captured by the complex/chaperone terms; bare protein binding is uninformative. Reason: The specific WDR83OS/Asterix interaction is better represented by the PAT complex (protein folding chaperone complex / multi-pass translocon complex) and chaperone annotations than by generic protein binding. Supporting Evidence: PMID:32814900 CCDC47 and Asterix form an obligate complex because knockdown or knockout of either protein results in substantial loss of the other |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from the OpenCell endogenous-tagging interactome/localization cartography is uninformative. Reason: High-throughput protein binding does not capture a specific CCDC47 function. |
| GO:0005791 rough endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Rough ER localization is consistent with CCDC47 being a ribosome-associated translocon factor. Reason: Consistent with the membrane-protein-biogenesis role at the ribosome-Sec61 channel of the rough ER. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt Rough endoplasmic reticulum membrane |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based ER annotation is consistent with the established ER residence of CCDC47. Reason: Direct localization evidence supports ER residence, the core compartment for CCDC47. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:32814900 An intramembrane chaperone complex facilitates membrane prot... | ACCEPT | Summary: Direct evidence places CCDC47 in the ER membrane as a single-pass component of the PAT complex. Reason: The PAT-complex study directly demonstrates CCDC47 as an ER membrane protein; this is the correct specific localization. Supporting Evidence: PMID:32814900 CCDC47 is an ER-resident single-pass membrane protein with a well-conserved cytosolic domain |
| GO:0045048 protein insertion into ER membrane | IDA PMID:32814900 An intramembrane chaperone complex facilitates membrane prot... | MODIFY | Summary: CCDC47 promotes biogenesis of multi-spanning membrane proteins as part of the PAT complex; the more specific multi-pass insertion term better captures this. Reason: The general ER protein-insertion term is correct but imprecise; CCDC47 acts specifically in multi-pass (polytopic) membrane protein insertion/biogenesis. Proposed replacements: multi-pass transmembrane protein insertion into ER membrane Supporting Evidence: PMID:32814900 Cells that lack either subunit of the PAT complex show reduced biogenesis of PMID:32814900 Thus, the PAT complex is an intramembrane chaperone that protects TMDs during assembly to minimize misfolding of multi-spanning membrane proteins and maintain cellular protein homeostasis. |
| GO:0101031 protein folding chaperone complex | IPI PMID:32814900 An intramembrane chaperone complex facilitates membrane prot... | ACCEPT | Summary: CCDC47 is part of the PAT intramembrane chaperone complex, captured well by this term. Reason: The obligate CCDC47-Asterix PAT complex functions as an intramembrane chaperone; this complex annotation is directly supported. Supporting Evidence: PMID:32814900 Here we identify the PAT complex, an abundant obligate heterodimer of the widely conserved ER-resident membrane proteins CCDC47 and Asterix. PMID:32814900 Thus, the PAT complex is an intramembrane chaperone that protects TMDs during assembly to minimize misfolding of multi-spanning membrane proteins and maintain cellular protein homeostasis. |
| GO:0160064 multi-pass translocon complex | IPI PMID:36261522 Substrate-driven assembly of a translocon for multipass memb... | ACCEPT | Summary: CCDC47 (within the PAT subcomplex) is a component of the multi-pass translocon; this is the most specific and accurate complex term. Reason: The multi-pass translocon study directly establishes the PAT complex (CCDC47/Asterix) as one of three accessory subcomplexes of the MPT. Supporting Evidence: PMID:36261522 This 'multipass translocon' is distinguished by three components that selectively bind the ribosome-Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:25009997 Contribution of calumin to embryogenesis through participati... | ACCEPT | Summary: Experimental evidence supports ER membrane localization of CCDC47/calumin. Reason: Consistent with established ER membrane residence. Supporting Evidence: PMID:25009997 Calumin is an endoplasmic reticulum (ER)-transmembrane protein |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:30401460 Bi-allelic CCDC47 Variants Cause a Disorder Characterized by... | ACCEPT | Summary: Experimental evidence supports ER membrane localization of CCDC47/calumin. Reason: Consistent with established ER membrane residence; this is the core compartment. Supporting Evidence: PMID:30401460 bi-allelic variants in CCDC47 that encodes the Ca2+-binding ER transmembrane protein CCDC47 |
| GO:0030867 rough endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Orthology-based rough ER membrane localization is consistent with the ribosome-associated translocon role. Reason: Consistent with experimental ER membrane localization and ribosome association. Supporting Evidence: file:human/CCDC47/CCDC47-uniprot.txt Rough endoplasmic reticulum membrane |
| GO:0160063 multi-pass transmembrane protein insertion into ER membrane | IDA PMID:36261522 Substrate-driven assembly of a translocon for multipass memb... | ACCEPT | Summary: This is the most precise core biological process for CCDC47 - facilitating insertion/biogenesis of multi-pass membrane proteins via the multi-pass translocon. Reason: Directly supported by reconstitution and depletion studies showing the multi-pass translocon components (including CCDC47/PAT) are required for multi-pass protein topogenesis and stability. Supporting Evidence: PMID:36261522 Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability. |
| GO:0160064 multi-pass translocon complex | IDA PMID:36261522 Substrate-driven assembly of a translocon for multipass memb... | ACCEPT | Summary: Direct structural/biochemical evidence places CCDC47 (PAT subcomplex) in the multi-pass translocon. Reason: The most specific and accurate complex localization for CCDC47, directly demonstrated. Supporting Evidence: PMID:36261522 This 'multipass translocon' is distinguished by three components that selectively bind the ribosome-Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. |
| GO:0005515 protein binding | IPI PMID:32820719 An ER translocon for multi-pass membrane protein biogenesis. | MARK AS OVER ANNOTATED | Summary: The meaningful interactions underlying this annotation are CCDC47's associations within the Sec61/MPT translocon; bare protein binding is uninformative. Reason: The specific translocon interactions are captured by the multi-pass translocon complex annotation; generic protein binding adds nothing. Supporting Evidence: PMID:32820719 Here we describe a ~ 360 kDa ribosome-associated complex comprising the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO complex. |
| GO:0043022 ribosome binding | IDA PMID:32820719 An ER translocon for multi-pass membrane protein biogenesis. | ACCEPT | Summary: CCDC47 is part of a ribosome-associated translocon assembly, supporting a ribosome-binding molecular function. Reason: Cryo-EM and biochemistry place CCDC47 within a ribosome-associated Sec61 translocon complex; ribosome binding is supported and relevant to co-translational multi-pass biogenesis. Supporting Evidence: PMID:32820719 Here we describe a ~ 360 kDa ribosome-associated complex comprising the core Sec61 channel and five accessory factors: TMCO1, CCDC47 and the Nicalin-TMEM147-NOMO complex. |
| GO:0044183 protein folding chaperone | IDA PMID:32814900 An intramembrane chaperone complex facilitates membrane prot... | ACCEPT | Summary: As part of the PAT intramembrane chaperone, CCDC47 contributes chaperone activity that protects nascent transmembrane domains during multi-pass biogenesis. Reason: The PAT complex is directly described as an intramembrane chaperone; CCDC47 is its scaffold/occluder subunit. Note Asterix is the substrate-contacting subunit, but the chaperone-function annotation at the protein level is appropriate. Supporting Evidence: PMID:32814900 Thus, the PAT complex is an intramembrane chaperone that protects TMDs during assembly to minimize misfolding of multi-spanning membrane proteins and maintain cellular protein homeostasis. |
| GO:0032469 endoplasmic reticulum calcium ion homeostasis | IMP PMID:30401460 Bi-allelic CCDC47 Variants Cause a Disorder Characterized by... | KEEP AS NON CORE | Summary: Patient-cell loss-of-function data directly support a role for CCDC47 in ER calcium homeostasis, but this is a secondary/contextual function. Reason: Reduced ER Ca2+ storage and impaired Ca2+ signaling in CCDC47-deficient cells support this process; retain as non-core relative to the membrane-biogenesis scaffold role. Supporting Evidence: PMID:30401460 In vitro cellular experiments showed decreased total ER Ca2+ storage, impaired Ca2+ signaling mediated by the IP3R Ca2+ release channel, and reduced ER Ca2+ refilling via store-operated Ca2+ entry. |
| GO:0036503 ERAD pathway | IMP PMID:25009997 Contribution of calumin to embryogenesis through participati... | KEEP AS NON CORE | Summary: Calumin co-IPs with ERAD machinery and its knockdown reduces ERAD efficiency, supporting involvement in ER-associated degradation as a secondary function. Reason: Experimental knockdown data link CCDC47/calumin to ERAD efficiency, but this is a contextual ER proteostasis role distinct from its core multi-pass biogenesis scaffold function. Supporting Evidence: PMID:25009997 calumin knockdown in HEK 293 cells resulted in ERAD being less efficient, as demonstrated by attenuation in both degradations of a misfolded Ξ±1-antitrypsin variant and the ER-to-cytosol dislocation of cholera toxin A1 subunit. |
| GO:0001649 osteoblast differentiation | HDA PMID:16210410 Differential expression profiling of membrane proteins by qu... | MARK AS OVER ANNOTATED | Summary: This annotation derives from detection of CCDC47 in a differential membrane-proteomics dataset of an MSC line during osteoblast differentiation, not from functional evidence. Reason: Presence in a high-throughput differential proteomics profile is not evidence that CCDC47 functions in osteoblast differentiation. Supporting Evidence: PMID:16210410 we used MS to characterize changes in expression of membrane protein markers before and after short-term induction of osteoblast (OB) differentiation |
| GO:0016020 membrane | HDA PMID:16210410 Differential expression profiling of membrane proteins by qu... | MARK AS OVER ANNOTATED | Summary: Generic membrane localization is subsumed by the specific ER membrane annotations. Reason: The bare membrane term is uninformative given direct, specific ER membrane localization evidence. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: Generic membrane localization from an NK-cell membrane-proteome dataset is uninformative. Reason: Subsumed by the specific ER membrane localization; bare membrane adds nothing. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: This annotation comes from a high-throughput mRNA interactome-capture atlas; there is no specific evidence of a physiological RNA-binding function for CCDC47. Reason: High-throughput crosslinking capture does not establish a meaningful RNA-binding molecular function for an ER membrane translocon scaffold. Supporting Evidence: PMID:22658674 Employing two complementary protocols for covalent UV crosslinking of RBPs to RNA, we describe a systematic, unbiased, and comprehensive approach, termed "interactome capture," to define the mRNA interactome of proliferating human HeLa cells. |
| GO:0160005 PAT complex | IPI PMID:32814900 An intramembrane chaperone complex facilitates membrane prot... | NEW | Summary: CCDC47 is a subunit of the obligate CCDC47-Asterix PAT intramembrane chaperone complex. Reason: The current review already accepts the broader multi-pass translocon complex; GO:0160005 is the exact PAT subcomplex term for the CCDC47/WDR83OS heterodimer and is more specific for CCDC47 than the parent MPT complex. Supporting Evidence: PMID:32814900 Here we identify the PAT complex, an abundant obligate heterodimer of the widely conserved ER-resident membrane proteins CCDC47 and Asterix. |
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Download this section (compressed HTML)Q: Does CCDC47 contribute catalytically/mechanistically to multi-pass biogenesis beyond stabilizing Asterix and occluding the Sec61 lateral gate, or is its role purely structural/scaffolding?
Q: Is the ER calcium homeostasis phenotype of CCDC47 deficiency a direct consequence of its Ca2+-binding capacity, or an indirect result of impaired biogenesis of calcium-handling membrane proteins?
Experiment: Perform proteome-wide and targeted membrane-protein stability/surface-expression assays (e.g., dual-color ratiometric reporters) in CCDC47-knockout versus rescued cells across diverse client topologies.
Hypothesis: CCDC47 is required specifically for biogenesis of a defined set of multi-pass membrane proteins (GPCRs, channels, transporters) but not single-pass or tail-anchored proteins.
Type: cell-based membrane protein biogenesis assay
Experiment: Quantify ER calcium stores and IP3R/SOCE-mediated signaling in CCDC47-null cells rescued with wild-type CCDC47 versus a Ca2+-binding-deficient mutant, and measure abundance/localization of key ER calcium channels.
Hypothesis: The ER calcium defect in CCDC47-deficient cells is secondary to mislocalization/instability of calcium-handling multi-pass channels rather than to direct loss of CCDC47 Ca2+ buffering.
Type: calcium imaging with structure-function rescue
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