Existing Annotations Review

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 α1-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.

Core Functions

CCDC47 is the scaffold subunit of the PAT intramembrane chaperone complex (an obligate heterodimer with WDR83OS/Asterix), a component of the ribosome-associated multi-pass translocon that promotes biogenesis of multi-pass (polytopic) membrane proteins downstream of Sec61. CCDC47 occludes the Sec61 lateral gate and stabilizes Asterix, which shields hydrophilic transmembrane segments of nascent clients until they fold.

Molecular Function:

protein folding chaperone

Directly Involved In:

multi-pass transmembrane protein insertion into ER membrane

Cellular Locations:

endoplasmic reticulum membrane

In Complex:

multi-pass translocon 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.
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.
PMID:36261522
Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability.

CCDC47/calumin contributes to ER calcium homeostasis as a low-affinity, high-capacity Ca2+-binding ER membrane protein; loss of function reduces ER calcium stores and impairs ER calcium signaling.

Molecular Function:

calcium ion binding

Directly Involved In:

endoplasmic reticulum calcium ion homeostasis

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

PMID:30401460
CCDC47, also known as calumin, has been shown to bind Ca2+ with low affinity and high capacity.
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.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

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:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16210410

Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:21903422

Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:25009997

Contribution of calumin to embryogenesis through participation in the endoplasmic reticulum-associated degradation activity.

Calumin co-IPs with ERAD machinery and its knockdown reduces ERAD efficiency.

"calumin knockdown in HEK 293 cells resulted in ERAD being less efficient, as demonstrated by attenuation in both degradations of a misfolded α1-antitrypsin variant and the ER-to-cytosol dislocation of cholera toxin A1 subunit."

PMID:30401460

Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.

CCDC47/calumin binds Ca2+ with low affinity and high capacity; biallelic loss causes a multisystem disorder with impaired ER calcium homeostasis.

"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."

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:32814900

An intramembrane chaperone complex facilitates membrane protein biogenesis.

CCDC47 and Asterix (WDR83OS) form the obligate PAT intramembrane chaperone complex that protects nascent TMDs during multi-pass membrane protein biogenesis.

"Here we identify the PAT complex, an abundant obligate heterodimer of the widely conserved ER-resident membrane proteins CCDC47 and Asterix."
Asterix is the substrate-contacting subunit; CCDC47 is the scaffold required for Asterix stability.

"Asterix is the substrate- interacting subunit of the PAT complex, while CCDC47 is needed for Asterix stability."

PMID:32820719

An ER translocon for multi-pass membrane protein biogenesis.

CCDC47 is a component of a ribosome-associated Sec61 multi-pass translocon assembly.

"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."

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36261522

Substrate-driven assembly of a translocon for multipass membrane proteins.

The PAT complex (CCDC47/Asterix) is one of three accessory subcomplexes of the substrate-recruited multi-pass translocon required for multi-pass protein topogenesis.

"Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability."

file:human/CCDC47/CCDC47-uniprot.txt

CCDC47 UniProtKB record (Q96A33)

file:human/CCDC47/CCDC47-notes.md

Manual CCDC47 curation notes

Suggested Experiments

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

📚 Additional Documentation

Notes

(CCDC47-notes.md)

CCDC47 (Q96A33) curation notes

Identity

HGNC: CCDC47; aka Calumin; "PAT complex subunit CCDC47" (UniProt RecName).
Single-pass type I ER membrane protein. Signal peptide 1-20; cytoplasmic 21-135; TM 136-155; lumenal 156-483. N-glycosylated at N178. Large lumenal domain with C-terminal disordered/coiled-coil basic region.
Disease: Trichohepatoneurodevelopmental syndrome (THNS, MIM:618268), autosomal recessive: woolly/coarse hair, liver dysfunction, dysmorphic features, hypotonia, global developmental delay. (This is the "CHISEL"/trichohepatoenteric-like phenotype referenced in the task.)

Core function: PAT complex / multipass translocon (MPT)

CCDC47 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: TMCO1+RAB5IF; BOS: NCLN+NOMO+TMEM147; PAT: CCDC47+Asterix) of the multipass translocon (MPT) that assembles around the ribosome–Sec61 channel during synthesis of multipass membrane proteins.

Note: Asterix, not CCDC47, directly contacts substrate TMDs; CCDC47's role is as the stable scaffold/occluder. The UniProt FUNCTION states CCDC47 "occludes the lateral gate of the SEC61 complex" (By similarity).

Multipass translocon membership and substrate-driven assembly

PMID:32820719
PMID:32820719
McGilvray et al. cryo-EM resolved CCDC47 residues 52-239 in complex with the translocon; CCDC47 is ribosome-associated within this assembly. The structure paper "An ER translocon for multi-pass membrane protein biogenesis" reports the architecture of a ribosome-bound TMCO1 translocon including CCDC47 (supports GO:0043022 ribosome binding, IDA, PMID:32820719).
PMID:36261522
PMID:36261522

UniProt FUNCTION synthesis: "Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes... The MPT complex takes over after the SEC61 complex... Within the PAT subcomplex, CCDC47 occludes the lateral gate of the SEC61 complex."

Secondary / contextual functions

ER calcium homeostasis

CCDC47/calumin binds Ca2+ with low affinity, high capacity; THNS patient cells show reduced ER Ca2+ stores and impaired Ca2+ signaling. This is plausibly a real role but is secondary to / partly downstream of its membrane-biogenesis scaffold function (loss of multipass membrane protein biogenesis would broadly perturb ER function).
- PMID:30401460
- PMID:30401460

ERAD

Mouse Ccdc47/calumin co-IPs with ERAD machinery (p97/VCP, BiP, derlin-1, derlin-2, VIMP/SELENOS); knockdown reduces ERAD efficiency. This connects CCDC47 to ER protein quality control / proteostasis more broadly.
- PMID:25009997
- PMID:25009997
- PMID:25009997 — embryonic lethality, essential for development/ER organization (UniProt: "essential role in the maintenance of ER organization during embryogenesis").

Over-annotations / non-core

GO:0005515 protein binding (IPI) from interactome / innate-immunity network papers (PMID:21903422, PMID:32814053, PMID:32814900, PMID:35271311) — bare "protein binding" is uninformative. Note PMID:32814900 is the PAT-complex discovery paper but the GOA "protein binding" annotation collapses the meaningful WDR83OS/Asterix interaction; the informative content is captured by the PAT complex (protein folding chaperone complex) and chaperone terms instead.
PMID:21903422 = innate immunity (IRF/STING) interaction network (CCDC47 a network node; IntAct lists IRF7, STING1, TIRAP, IRAK1). Not a core function.
PMID:35271311 = OpenCell endogenous tagging cartography (high-throughput localization/interaction map).
PMID:32814053 = neurodegenerative-disease interactome map (high-throughput).
GO:0003723 RNA binding (HDA, PMID:22658674) — from the mRNA-interactome capture atlas; high-throughput RBP capture, not a demonstrated specific RNA-binding function for CCDC47.
GO:0001649 osteoblast differentiation (HDA, PMID:16210410) — from a quantitative membrane-proteome profiling of an MSC line during osteoblast differentiation; presence in a differential proteomics dataset, not evidence CCDC47 functions in osteoblast differentiation.
GO:0016020 membrane (HDA, PMID:16210410, PMID:19946888) — generic; subsumed by the specific ER membrane terms.
GO:0005509 calcium ion binding — IBA (GO_REF:0000033) and IEA (GO_REF:0000120). Supported by the low-affinity/high-capacity Ca2+ binding of calumin (PMID:30401460); retain but as non-core (a property contributing to ER Ca2+ buffering rather than the central biogenesis role).

Localization

Well supported: ER membrane / rough ER membrane (multiple EXP/IDA: PMID:25009997, PMID:30401460, PMID:32814900). Core. RNA-seq / interactome localizations consistent.

Summary of action plan

CORE: PAT complex / MPT membership (GO:0160064 multi-pass translocon complex; GO:0101031 protein folding chaperone complex), multi-pass transmembrane protein insertion into ER membrane (GO:0160063), protein folding chaperone (GO:0044183), ribosome binding (GO:0043022), ER membrane localization (GO:0005789), endoplasmic reticulum (GO:0005783).
NON-CORE (real but secondary): ER calcium ion homeostasis (GO:0032469), calcium ion binding (GO:0005509), ERAD pathway (GO:0036503).
OVER-ANNOTATED: bare protein binding, RNA binding, osteoblast differentiation, generic membrane.
MODIFY: GO:0045048 protein insertion into ER membrane (general) and GO:0006457 protein folding (general) -> replace with the specific multi-pass insertion term GO:0160063.

Pn Notes

(CCDC47-pn-notes.md)

CCDC47 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96A33
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/CCDC47/CCDC47-ai-review.yaml
AIGR review HTML: present - genes/human/CCDC47/CCDC47-ai-review.html
Gene notes: present - genes/human/CCDC47/CCDC47-notes.md
GOA TSV: present - genes/human/CCDC47/CCDC47-goa.tsv
UniProt record: present - genes/human/CCDC47/CCDC47-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CCDC47.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CCDC47.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

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

AIGR Review Snapshot

Description: 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).
Existing/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 5; MARK_AS_OVER_ANNOTATED: 9; MODIFY: 2

PN Consistency Summary

Consistency: Highly consistent. Review, notes, and PN all identify CCDC47 as the scaffold subunit of the PAT intramembrane-chaperone complex (obligate heterodimer with WDR83OS/Asterix) within the ribosome-associated multi-pass translocon (MPT). No contradictions.
PN story / NEW pressure: GO:0160005 "PAT complex" is VERIFIED real (OLS def names CCDC47+Asterix heterodimer) and is NOT in CCDC47's GOA or review — the review used the broader parent GO:0160064 multi-pass translocon complex (IDA, PMID:36261522) and GO:0101031 protein folding chaperone complex. GO:0160005 is strictly more specific and exactly correct. Conclude: defensible ADD (the precise complex term). GO:0044743 / GO:0015031 are broader generalizations (transmembrane import / protein transport) that the review covers more specifically via GO:0160063 multi-pass TM insertion + GO:0045048 — already captured / broader.
Evidence alignment: PN node carries no reference titles; review/GOA anchored on the defining primary literature (PMID:32814900 PAT discovery, PMID:36261522 MPT assembly, PMID:32820719 ribosome-Sec61 translocon). The PAT-complex term itself originates from this same literature, so PN and review are evidence-aligned even without shared citation strings.
Verdict: Consistent; PN adds the precise complex term. Recommended edits: [YAML] ADD GO:0160005 PAT complex (part_of, IPI/IDA, PMID:32814900/PMID:36261522) to CCDC47 existing_annotations and core_functions.in_complex — it is the exact, more-specific complex vs the review's GO:0160064. [MAP] keep GO:0044743/GO:0015031 as context-only (broader than review's GO:0160063/GO:0045048).

Full Consistency Review

UniProt: Q96A33 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (excellent; review independently lands on PAT/MPT biology, notes present)
PN placement: ER proteostasis|Protein transport|Transmembrane protein import|PAT complex component ; PN-node mapping: type (PAT complex component)→GO:0160005 PAT complex (mapped/ok); group (Transmembrane protein import)→GO:0044743 protein transmembrane import into intracellular organelle (mapped/ok); class (Protein transport)→GO:0015031 protein transport (mapped/ok).
Consistency: Highly consistent. Review, notes, and PN all identify CCDC47 as the scaffold subunit of the PAT intramembrane-chaperone complex (obligate heterodimer with WDR83OS/Asterix) within the ribosome-associated multi-pass translocon (MPT). No contradictions.
PN story / NEW pressure: GO:0160005 "PAT complex" is VERIFIED real (OLS def names CCDC47+Asterix heterodimer) and is NOT in CCDC47's GOA or review — the review used the broader parent GO:0160064 multi-pass translocon complex (IDA, PMID:36261522) and GO:0101031 protein folding chaperone complex. GO:0160005 is strictly more specific and exactly correct. Conclude: defensible ADD (the precise complex term). GO:0044743 / GO:0015031 are broader generalizations (transmembrane import / protein transport) that the review covers more specifically via GO:0160063 multi-pass TM insertion + GO:0045048 — already captured / broader.
Mapping strategy: Node mapping is sound and laddered correctly (specific complex at type, broad process at class). The class/group terms are broader than the review (precedent: TOMM20/HSPA8/RAB7A broader-than-review rejections) — treat GO:0044743/GO:0015031 as context-only, not as gene-level GO assertions superseding the review's specific terms. The type-level GO:0160005 is the value-add.
Evidence alignment: PN node carries no reference titles; review/GOA anchored on the defining primary literature (PMID:32814900 PAT discovery, PMID:36261522 MPT assembly, PMID:32820719 ribosome-Sec61 translocon). The PAT-complex term itself originates from this same literature, so PN and review are evidence-aligned even without shared citation strings.
Verdict: Consistent; PN adds the precise complex term. Recommended edits: [YAML] ADD GO:0160005 PAT complex (part_of, IPI/IDA, PMID:32814900/PMID:36261522) to CCDC47 existing_annotations and core_functions.in_complex — it is the exact, more-specific complex vs the review's GO:0160064. [MAP] keep GO:0044743/GO:0015031 as context-only (broader than review's GO:0160063/GO:0045048).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/CCDC47/CCDC47-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Protein transport | Transmembrane protein import | PAT complex component

UniProt: Q96A33
In branches: ER
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Protein transport|Transmembrane protein import|PAT complex component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0160005 PAT complex]
  rationale: This PN type denotes PAT-complex components in ER membrane protein insertion. The GO PAT complex term is the direct target.
- [group] ER proteostasis|Protein transport|Transmembrane protein import
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0044743 protein transmembrane import into intracellular organelle]
  rationale: This PN group covers ER transmembrane-protein insertion/import systems such as EMC- and PAT-related pathways. The local GO cache does not expose an ER-specific matching term, so the broader intracellular-organelle transmembrane-import process is the best supported propagation target.
- [class] ER proteostasis|Protein transport
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0015031 protein transport]
  rationale: The PN ER Protein transport class groups ER-targeting and ER-insertion pathways. GO protein transport is the appropriate propagation target, while the source class remains ER-specific and broader than any single GO transport subtype.
- [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 (3)

GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
GO:0044743 protein transmembrane import into intracellular organelle | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport|Transmembrane protein import
GO:0160005 PAT complex | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=ER proteostasis|Protein transport|Transmembrane protein import|PAT complex component

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: Q96A33
gene_symbol: CCDC47
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: '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).'
alternative_products:
- name: '1'
  id: Q96A33-1
- name: '2'
  id: Q96A33-2
  sequence_note: VSP_018478
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ER localization is well supported and is the compartment where CCDC47
      performs its core membrane-biogenesis scaffold function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
    - reference_id: PMID:32814900
      supporting_text: CCDC47 is an ER-resident single-pass membrane protein with a
        well-conserved cytosolic domain
      reference_section_type: RESULTS
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: CCDC47, also known as calumin, has been shown to bind Ca2+ with
        low affinity and high capacity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated transfer of calcium ion binding agrees with experimental low-affinity,
      high-capacity Ca2+ binding by CCDC47/calumin.
    action: KEEP_AS_NON_CORE
    reason: Consistent with experimental evidence; retained as non-core relative to
      the membrane-biogenesis scaffold function.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: CCDC47, also known as calumin, has been shown to bind Ca2+ with
        low affinity and high capacity.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Automated ER localization is consistent with direct experimental evidence.
    action: ACCEPT
    reason: ER residence is well established and is core to CCDC47 function.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization is the precise, well-supported compartment for
      this single-pass type I membrane protein.
    action: ACCEPT
    reason: Direct experimental and structural evidence place CCDC47 in the ER membrane
      as part of the translocon; this is the correct specific localization term.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
    - reference_id: PMID:32814900
      supporting_text: CCDC47 is an ER-resident single-pass membrane protein with a
        well-conserved cytosolic domain
      reference_section_type: RESULTS
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0160063
      label: multi-pass transmembrane protein insertion into ER membrane
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0030867
    label: rough endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Rough ER membrane is consistent with CCDC47 being a ribosome-associated
      translocon component.
    action: ACCEPT
    reason: CCDC47 is part of a ribosome-bound (rough ER) translocon assembly; the
      rough ER membrane localization is appropriate.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: Rough endoplasmic reticulum membrane
      reference_section_type: OTHER
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: ER calcium homeostasis is supported by patient-cell data showing reduced
      ER calcium stores, but is secondary to the biogenesis scaffold function.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  qualifier: enables
  review:
    summary: Generic protein binding from an innate-immunity interaction network is
      uninformative for CCDC47 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding from a high-throughput interactome does not capture
      a physiologically interpretable CCDC47 function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein binding from a neurodegenerative-disease interactome map
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not identify a specific CCDC47 molecular
      function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814900
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: CCDC47 and Asterix form an obligate complex because knockdown
        or knockout of either protein results in substantial loss of the other
      reference_section_type: RESULTS
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Generic protein binding from the OpenCell endogenous-tagging interactome/localization
      cartography is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not capture a specific CCDC47 function.
- term:
    id: GO:0005791
    label: rough endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Rough ER localization is consistent with CCDC47 being a ribosome-associated
      translocon factor.
    action: ACCEPT
    reason: Consistent with the membrane-protein-biogenesis role at the ribosome-Sec61
      channel of the rough ER.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: Rough endoplasmic reticulum membrane
      reference_section_type: OTHER
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based ER annotation is consistent with the established
      ER residence of CCDC47.
    action: ACCEPT
    reason: Direct localization evidence supports ER residence, the core compartment
      for CCDC47.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:32814900
  qualifier: located_in
  review:
    summary: Direct evidence places CCDC47 in the ER membrane as a single-pass component
      of the PAT complex.
    action: ACCEPT
    reason: The PAT-complex study directly demonstrates CCDC47 as an ER membrane protein;
      this is the correct specific localization.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: CCDC47 is an ER-resident single-pass membrane protein with a
        well-conserved cytosolic domain
      reference_section_type: RESULTS
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:32814900
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    reason: The general ER protein-insertion term is correct but imprecise; CCDC47
      acts specifically in multi-pass (polytopic) membrane protein insertion/biogenesis.
    proposed_replacement_terms:
    - id: GO:0160063
      label: multi-pass transmembrane protein insertion into ER membrane
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: Cells that lack either subunit of the PAT complex show reduced
        biogenesis of
      reference_section_type: ABSTRACT
    - reference_id: PMID:32814900
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0101031
    label: protein folding chaperone complex
  evidence_type: IPI
  original_reference_id: PMID:32814900
  qualifier: part_of
  review:
    summary: CCDC47 is part of the PAT intramembrane chaperone complex, captured well
      by this term.
    action: ACCEPT
    reason: The obligate CCDC47-Asterix PAT complex functions as an intramembrane chaperone;
      this complex annotation is directly supported.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: Here we identify the PAT complex, an abundant obligate heterodimer
        of the widely conserved ER-resident membrane proteins CCDC47 and Asterix.
      reference_section_type: ABSTRACT
    - reference_id: PMID:32814900
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0160064
    label: multi-pass translocon complex
  evidence_type: IPI
  original_reference_id: PMID:36261522
  qualifier: part_of
  review:
    summary: CCDC47 (within the PAT subcomplex) is a component of the multi-pass translocon;
      this is the most specific and accurate complex term.
    action: ACCEPT
    reason: The multi-pass translocon study directly establishes the PAT complex (CCDC47/Asterix)
      as one of three accessory subcomplexes of the MPT.
    supported_by:
    - reference_id: PMID:36261522
      supporting_text: '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.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:25009997
  qualifier: located_in
  review:
    summary: Experimental evidence supports ER membrane localization of CCDC47/calumin.
    action: ACCEPT
    reason: Consistent with established ER membrane residence.
    supported_by:
    - reference_id: PMID:25009997
      supporting_text: Calumin is an endoplasmic reticulum (ER)-transmembrane protein
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:30401460
  qualifier: located_in
  review:
    summary: Experimental evidence supports ER membrane localization of CCDC47/calumin.
    action: ACCEPT
    reason: Consistent with established ER membrane residence; this is the core compartment.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: bi-allelic variants in CCDC47 that encodes the Ca2+-binding
        ER transmembrane protein CCDC47
      reference_section_type: ABSTRACT
- term:
    id: GO:0030867
    label: rough endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Orthology-based rough ER membrane localization is consistent with the
      ribosome-associated translocon role.
    action: ACCEPT
    reason: Consistent with experimental ER membrane localization and ribosome association.
    supported_by:
    - reference_id: file:human/CCDC47/CCDC47-uniprot.txt
      supporting_text: Rough endoplasmic reticulum membrane
      reference_section_type: OTHER
- term:
    id: GO:0160063
    label: multi-pass transmembrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:36261522
  qualifier: involved_in
  review:
    summary: This is the most precise core biological process for CCDC47 - facilitating
      insertion/biogenesis of multi-pass membrane proteins via the multi-pass translocon.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:36261522
      supporting_text: Reconstitution studies demonstrate a role for multipass translocon
        components in protein topogenesis, and cells lacking these components show
        reduced multipass protein stability.
      reference_section_type: ABSTRACT
- term:
    id: GO:0160064
    label: multi-pass translocon complex
  evidence_type: IDA
  original_reference_id: PMID:36261522
  qualifier: part_of
  review:
    summary: Direct structural/biochemical evidence places CCDC47 (PAT subcomplex)
      in the multi-pass translocon.
    action: ACCEPT
    reason: The most specific and accurate complex localization for CCDC47, directly
      demonstrated.
    supported_by:
    - reference_id: PMID:36261522
      supporting_text: '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.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32820719
  qualifier: enables
  review:
    summary: The meaningful interactions underlying this annotation are CCDC47's associations
      within the Sec61/MPT translocon; bare protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific translocon interactions are captured by the multi-pass translocon
      complex annotation; generic protein binding adds nothing.
    supported_by:
    - reference_id: PMID:32820719
      supporting_text: '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.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0043022
    label: ribosome binding
  evidence_type: IDA
  original_reference_id: PMID:32820719
  qualifier: enables
  review:
    summary: CCDC47 is part of a ribosome-associated translocon assembly, supporting
      a ribosome-binding molecular function.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:32820719
      supporting_text: '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.'
      reference_section_type: ABSTRACT
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:32814900
  qualifier: enables
  review:
    summary: As part of the PAT intramembrane chaperone, CCDC47 contributes chaperone
      activity that protects nascent transmembrane domains during multi-pass biogenesis.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:32814900
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  evidence_type: IMP
  original_reference_id: PMID:30401460
  qualifier: involved_in
  review:
    summary: Patient-cell loss-of-function data directly support a role for CCDC47
      in ER calcium homeostasis, but this is a secondary/contextual function.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:30401460
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:25009997
  qualifier: involved_in
  review:
    summary: Calumin co-IPs with ERAD machinery and its knockdown reduces ERAD efficiency,
      supporting involvement in ER-associated degradation as a secondary function.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:25009997
      supporting_text: calumin knockdown in HEK 293 cells resulted in ERAD being less
        efficient, as demonstrated by attenuation in both degradations of a misfolded
        α1-antitrypsin variant and the ER-to-cytosol dislocation of cholera toxin A1
        subunit.
      reference_section_type: ABSTRACT
- term:
    id: GO:0001649
    label: osteoblast differentiation
  evidence_type: HDA
  original_reference_id: PMID:16210410
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: Presence in a high-throughput differential proteomics profile is not evidence
      that CCDC47 functions in osteoblast differentiation.
    supported_by:
    - reference_id: PMID:16210410
      supporting_text: we used MS to characterize changes in expression of membrane
        protein markers before and after short-term induction of osteoblast (OB) differentiation
      reference_section_type: ABSTRACT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:16210410
  qualifier: located_in
  review:
    summary: Generic membrane localization is subsumed by the specific ER membrane
      annotations.
    action: MARK_AS_OVER_ANNOTATED
    reason: The bare membrane term is uninformative given direct, specific ER membrane
      localization evidence.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Generic membrane localization from an NK-cell membrane-proteome dataset
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Subsumed by the specific ER membrane localization; bare membrane adds nothing.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput crosslinking capture does not establish a meaningful RNA-binding
      molecular function for an ER membrane translocon scaffold.
    supported_by:
    - reference_id: PMID:22658674
      supporting_text: '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.'
      reference_section_type: ABSTRACT
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  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:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16210410
  title: Differential expression profiling of membrane proteins by quantitative proteomics
    in a human mesenchymal stem cell line undergoing osteoblast differentiation.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating
    type I interferon production.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:25009997
  title: Contribution of calumin to embryogenesis through participation in the endoplasmic
    reticulum-associated degradation activity.
  findings:
  - statement: Calumin co-IPs with ERAD machinery and its knockdown reduces ERAD efficiency.
    supporting_text: calumin knockdown in HEK 293 cells resulted in ERAD being less
      efficient, as demonstrated by attenuation in both degradations of a misfolded
      α1-antitrypsin variant and the ER-to-cytosol dislocation of cholera toxin A1
      subunit.
    reference_section_type: ABSTRACT
- id: PMID:30401460
  title: Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair,
    Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay.
  findings:
  - statement: CCDC47/calumin binds Ca2+ with low affinity and high capacity; biallelic
      loss causes a multisystem disorder with impaired ER calcium homeostasis.
    supporting_text: 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.
    reference_section_type: ABSTRACT
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:32814900
  title: An intramembrane chaperone complex facilitates membrane protein biogenesis.
  findings:
  - statement: CCDC47 and Asterix (WDR83OS) form the obligate PAT intramembrane chaperone
      complex that protects nascent TMDs during multi-pass membrane protein biogenesis.
    supporting_text: Here we identify the PAT complex, an abundant obligate heterodimer
      of the widely conserved ER-resident membrane proteins CCDC47 and Asterix.
    reference_section_type: ABSTRACT
  - statement: Asterix is the substrate-contacting subunit; CCDC47 is the scaffold
      required for Asterix stability.
    supporting_text: Asterix is the substrate- interacting subunit of the PAT complex,
      while CCDC47 is needed for Asterix stability.
    reference_section_type: RESULTS
- id: PMID:32820719
  title: An ER translocon for multi-pass membrane protein biogenesis.
  findings:
  - statement: CCDC47 is a component of a ribosome-associated Sec61 multi-pass translocon
      assembly.
    supporting_text: '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.'
    reference_section_type: ABSTRACT
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:36261522
  title: Substrate-driven assembly of a translocon for multipass membrane proteins.
  findings:
  - statement: The PAT complex (CCDC47/Asterix) is one of three accessory subcomplexes
      of the substrate-recruited multi-pass translocon required for multi-pass protein
      topogenesis.
    supporting_text: Reconstitution studies demonstrate a role for multipass translocon
      components in protein topogenesis, and cells lacking these components show reduced
      multipass protein stability.
    reference_section_type: ABSTRACT
- id: file:human/CCDC47/CCDC47-uniprot.txt
  title: CCDC47 UniProtKB record (Q96A33)
  findings: []
- id: file:human/CCDC47/CCDC47-notes.md
  title: Manual CCDC47 curation notes
  findings: []
core_functions:
- description: CCDC47 is the scaffold subunit of the PAT intramembrane chaperone complex
    (an obligate heterodimer with WDR83OS/Asterix), a component of the ribosome-associated
    multi-pass translocon that promotes biogenesis of multi-pass (polytopic) membrane
    proteins downstream of Sec61. CCDC47 occludes the Sec61 lateral gate and stabilizes
    Asterix, which shields hydrophilic transmembrane segments of nascent clients until
    they fold.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0160063
    label: multi-pass transmembrane protein insertion into ER membrane
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0160064
    label: multi-pass translocon complex
  supported_by:
  - reference_id: PMID:32814900
    supporting_text: Here we identify the PAT complex, an abundant obligate heterodimer
      of the widely conserved ER-resident membrane proteins CCDC47 and Asterix.
    reference_section_type: ABSTRACT
  - reference_id: PMID:32814900
    supporting_text: 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.
    reference_section_type: ABSTRACT
  - reference_id: PMID:36261522
    supporting_text: Reconstitution studies demonstrate a role for multipass translocon
      components in protein topogenesis, and cells lacking these components show reduced
      multipass protein stability.
    reference_section_type: ABSTRACT
- description: CCDC47/calumin contributes to ER calcium homeostasis as a low-affinity,
    high-capacity Ca2+-binding ER membrane protein; loss of function reduces ER calcium
    stores and impairs ER calcium signaling.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  directly_involved_in:
  - id: GO:0032469
    label: endoplasmic reticulum calcium ion homeostasis
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:30401460
    supporting_text: CCDC47, also known as calumin, has been shown to bind Ca2+ with
      low affinity and high capacity.
    reference_section_type: ABSTRACT
  - reference_id: PMID:30401460
    supporting_text: 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.
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
suggested_experiments:
- 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.
  description: 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.
  experiment_type: cell-based membrane protein biogenesis assay
- 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.
  description: 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.
  experiment_type: calcium imaging with structure-function rescue

CCDC47

Gene Description