Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0043529 GET complex	IBA GO_REF:0000033	ACCEPT	Summary: CAML is a core component of the GET insertase complex (with WRB/GET1 and TRC40/GET3); this is the central, well-supported localization. Reason: Direct experimental and structural evidence establish CAML as a subunit of the GET complex; phylogenetic transfer is correct. Supporting Evidence: PMID:23041287 We identify calcium-modulating cyclophilin ligand (CAML) as a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA proteins, and show that CAML mediates membrane insertion of TA proteins.
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IBA GO_REF:0000033	ACCEPT	Summary: This is the core biological process for CAML - post-translational insertion of tail-anchored membrane proteins into the ER membrane. Reason: Directly supported by reconstitution and depletion studies; the most specific and accurate process term for CAML. Supporting Evidence: PMID:23041287 We identify calcium-modulating cyclophilin ligand (CAML) as a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA proteins, and show that CAML mediates membrane insertion of TA proteins.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: ER membrane is the precise, well-supported localization for this multi-pass ER membrane protein. Reason: Direct experimental evidence places CAML in the ER membrane as part of the GET insertase; the specific localization is correct. Supporting Evidence: file:human/CAMLG/CAMLG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:15451437 Immediate early gene X-1 interacts with proteins that modula...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a yeast two-hybrid apoptosis screen (IEX-1 interaction) is uninformative. Reason: Bare protein binding does not capture a physiologically interpretable CAML function.
GO:0005515 protein binding	IPI PMID:16243292 Fibrocystin interacts with CAML, a protein involved in Ca2+ ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a fibrocystin yeast two-hybrid interaction is uninformative. Reason: Bare protein binding does not capture a specific CAML molecular function.
GO:0005515 protein binding	IPI PMID:22046132 The SARS-coronavirus-host interactome: identification of cyc...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a SARS-coronavirus host-interactome screen is uninformative. Reason: High-throughput protein binding does not identify a specific CAML function.
GO:0005515 protein binding	IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a membrane two-hybrid (MaMTH) assay is uninformative. Reason: Bare protein binding does not capture a specific CAML function.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a proteome-scale interactome map is uninformative. Reason: High-throughput interactome protein binding does not capture a specific CAML function.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an interactome architecture map is uninformative. Reason: High-throughput protein binding adds no specific functional information.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from an EGFR-network rewiring interactome is uninformative. Reason: Bare protein binding does not capture a specific CAML function; any EGFR-related role is contextual.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a binary interactome reference map is uninformative. Reason: High-throughput protein binding adds no specific functional information.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a dual proteome-scale interactome network is uninformative. Reason: High-throughput protein binding does not capture a specific CAML function.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a multimodal cell-map interactome is uninformative. Reason: High-throughput protein binding does not capture a specific CAML function.
GO:0001782 B cell homeostasis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CAML is reported to be essential for survival of peripheral follicular B cells (mouse), a contextual cell-type-specific role rather than its core molecular function. Reason: Supported by orthologous/by-similarity evidence and the TACI interaction, but secondary to the core GET insertase function; retain as non-core. Supporting Evidence: file:human/CAMLG/CAMLG-uniprot.txt peripheral follicular B cells
GO:0005789 endoplasmic reticulum membrane	EXP PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: Experimental evidence supports ER membrane localization of CAML as part of the TA insertion machinery. Reason: Consistent with the core ER membrane GET insertase role. Supporting Evidence: PMID:23041287 posttranslationally inserted into the endoplasmic reticulum
GO:0005789 endoplasmic reticulum membrane	NAS PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: ER membrane localization is consistent with the structural characterization of the WRB/CAML/TRC40 insertase. Reason: The correct specific localization, consistent with all experimental and structural data. Supporting Evidence: PMID:32910895 targets and inserts tail-anchored (TA)
GO:0043529 GET complex	IPI PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: Structural study directly establishes CAML as a subunit of the WRB/CAML/TRC40 GET insertase complex. Reason: Cryo-EM and native MS of the human WRB/CAML/TRC40 complex directly support GET complex membership. Supporting Evidence: PMID:32910895 mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes
GO:0045048 protein insertion into ER membrane	NAS PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: CAML mediates insertion of tail-anchored proteins into the ER membrane; this general term is correct and the more specific tail-anchored term is also annotated. Reason: Directly supported; this is a parent of the more specific tail-anchored insertion term and accurately describes CAML's role. Supporting Evidence: PMID:23041287 CAML and WRB synergistically insert TA proteins into the
GO:0005515 protein binding	IPI PMID:31417168 The WRB Subunit of the Get3 Receptor is Required for the Cor...	MARK AS OVER ANNOTATED	Summary: The meaningful interaction here is CAML-WRB; bare protein binding is uninformative. Reason: The specific WRB interaction is captured by the GET complex annotation; generic protein binding adds nothing. Supporting Evidence: PMID:31417168 WRB and CAML depend
GO:0005515 protein binding	IPI PMID:32187542 Differential Modes of Orphan Subunit Recognition for the WRB...	MARK AS OVER ANNOTATED	Summary: The meaningful interaction is CAML-WRB within the insertase; bare protein binding is uninformative. Reason: The specific WRB/CAML interaction is captured by the GET complex annotation; generic protein binding adds nothing. Supporting Evidence: PMID:32187542 an essential insertase
GO:0005789 endoplasmic reticulum membrane	IDA PMID:31417168 The WRB Subunit of the Get3 Receptor is Required for the Cor...	ACCEPT	Summary: Direct evidence places CAML in the ER membrane with a defined three-TM C-terminal topology. Reason: This study experimentally established CAML ER membrane integration and topology; the localization is core and accurate. Supporting Evidence: PMID:31417168 transmembrane segments (TMs) in its C-terminal region
GO:0050821 protein stabilization	IDA PMID:32187542 Differential Modes of Orphan Subunit Recognition for the WRB...	KEEP AS NON CORE	Summary: CAML and WRB reciprocally stabilize each other's correct folding/topology within the insertase, supporting a protein stabilization role. Reason: Reciprocal stabilization of WRB is well supported but is an aspect of complex assembly downstream of the core insertase function; retain as non-core. Supporting Evidence: PMID:32187542 When present, WRB can correct the topology of CAML both in vitro and in cells.
GO:0043529 GET complex	IDA PMID:32910895 Structural Basis of Tail-Anchored Membrane Protein Biogenesi...	ACCEPT	Summary: Direct structural evidence establishes CAML as a GET complex subunit. Reason: Cryo-EM of the human WRB/CAML/TRC40 complex directly supports GET complex membership. Supporting Evidence: PMID:32910895 mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes
GO:0001782 B cell homeostasis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Orthology-based B cell homeostasis annotation reflects the mouse follicular B cell survival phenotype; contextual rather than core. Reason: Supported by orthology and the TACI interaction but secondary to the GET insertase molecular function. Supporting Evidence: file:human/CAMLG/CAMLG-uniprot.txt peripheral follicular B cells
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IDA PMID:27226539 Tail-anchored Protein Insertion in Mammals: FUNCTION AND REC...	ACCEPT	Summary: Reconstitution shows CAML (with WRB) is required and sufficient to confer tail-anchored protein insertion competence to liposomes. Reason: Strong direct biochemical evidence for the core insertion process. Supporting Evidence: PMID:27226539 in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes
GO:0005783 endoplasmic reticulum	IDA PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: ER localization is well supported and is the core compartment for CAML function. Reason: Consistent with the more specific ER membrane localization and the insertase role. Supporting Evidence: PMID:23041287 posttranslationally inserted into the endoplasmic reticulum
GO:0043529 GET complex	IPI PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: CAML is identified as the mammal-specific subunit of the TRC40/GET receptor complex with WRB. Reason: Directly demonstrated GET complex membership. Supporting Evidence: PMID:23041287 and WRB as components of the TRC40 receptor complex
GO:0071816 tail-anchored membrane protein insertion into ER membrane	IMP PMID:23041287 Molecular machinery for insertion of tail-anchored membrane ...	ACCEPT	Summary: Mutagenesis/perturbation data support CAML's requirement for tail-anchored protein insertion into the ER membrane. Reason: Loss-of-function/mutagenesis evidence directly supports the core insertion process. Supporting Evidence: PMID:23041287 binding of TRC40 to CAML is
GO:0005737 cytoplasm	IDA PMID:20553626 RNF122: a novel ubiquitin ligase associated with calcium-mod...	MARK AS OVER ANNOTATED	Summary: CAML is an integral ER membrane protein with a large cytoplasmic domain; a bare cytoplasm localization is misleading relative to the established ER membrane residence. Reason: Although CAML has cytosol-facing regions, it is an ER membrane protein; the ER membrane terms are the accurate localization and bare cytoplasm over-states a soluble distribution. Supporting Evidence: file:human/CAMLG/CAMLG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0031397 negative regulation of protein ubiquitination	IMP PMID:20553626 RNF122: a novel ubiquitin ligase associated with calcium-mod...	KEEP AS NON CORE	Summary: This derives from a single study where CAML stabilizes the E3 ligase RNF122; it is a narrow, context-specific finding rather than a core CAML function. Reason: Supported by the RNF122 co-IP study but represents a specific accessory interaction, not the conserved GET insertase function. Supporting Evidence: PMID:20553626 it stabilizes RNF122
GO:0031625 ubiquitin protein ligase binding	IPI PMID:20553626 RNF122: a novel ubiquitin ligase associated with calcium-mod...	KEEP AS NON CORE	Summary: CAML binds the RING E3 ligase RNF122; a specific but context-limited single-study interaction. Reason: This specific binding (to RNF122) is supported and more informative than bare protein binding, but it is not the core GET function. Supporting Evidence: PMID:20553626 identified calcium-modulating cyclophilin ligand (CAML) as an
GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process	IMP PMID:20553626 RNF122: a novel ubiquitin ligase associated with calcium-mod...	KEEP AS NON CORE	Summary: This derives from the same RNF122 stabilization study; a narrow, context-specific finding rather than a core CAML function. Reason: Supported by the RNF122 study (CAML stabilizes RNF122) but secondary to the core insertase function. Supporting Evidence: PMID:20553626 it stabilizes RNF122
GO:0050821 protein stabilization	IMP PMID:20553626 RNF122: a novel ubiquitin ligase associated with calcium-mod...	KEEP AS NON CORE	Summary: CAML stabilizes RNF122 in this single study; a context-specific accessory role rather than core function. Reason: Supported but narrow; the more general/relevant stabilization role is the reciprocal WRB/CAML stabilization within the insertase. Supporting Evidence: PMID:20553626 it stabilizes RNF122
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 subsumed by the specific ER membrane terms. Reason: Bare membrane is uninformative given direct, specific ER membrane localization.
GO:0005783 endoplasmic reticulum	IDA PMID:12919676 CAML is required for efficient EGF receptor recycling.	ACCEPT	Summary: ER localization is supported; consistent with the core ER residence of CAML. Reason: Direct localization evidence consistent with the established ER membrane residence. Supporting Evidence: file:human/CAMLG/CAMLG-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0006952 defense response	TAS PMID:7522304 Calcium signalling in T cells stimulated by a cyclophilin B-...	MARK AS OVER ANNOTATED	Summary: This broad term derives from the original discovery of CAML as a calcium-signaling modulator activating NF-AT/IL-2 in T cells; it is contextual and over-broad relative to the core insertase function. Reason: The underlying evidence is T-cell calcium signaling, not a defined defense-response function; this broad BP term overstates the role of canonical CAML. Supporting Evidence: PMID:7522304 acts downstream of the TCR and upstream of
GO:0007165 signal transduction	TAS PMID:7522304 Calcium signalling in T cells stimulated by a cyclophilin B-...	MARK AS OVER ANNOTATED	Summary: CAML was originally described as a calcium-signal modulator in T cells, but generic signal transduction is over-broad and is not the core conserved function. Reason: The historical calcium-signaling role is contextual; the broad signal transduction term is uninformative relative to the established GET insertase function. Supporting Evidence: PMID:7522304 causing an influx of calcium

Core Functions

CAML is a core subunit of the GET (guided entry of tail-anchored proteins) insertase complex. Together with WRB/GET1 it forms the ER membrane receptor for the cytosolic ATPase TRC40/GET3 and mediates post-translational insertion of tail-anchored membrane proteins into the ER membrane.

Directly Involved In:

tail-anchored membrane protein insertion into ER membrane

Cellular Locations:

endoplasmic reticulum membrane

In Complex:

GET complex

Supporting Evidence:

PMID:23041287
We identify calcium-modulating cyclophilin ligand (CAML) as a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA proteins, and show that CAML mediates membrane insertion of TA proteins.
PMID:27226539
in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes
PMID:32910895
mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes

References

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:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:7522304

Calcium signalling in T cells stimulated by a cyclophilin B-binding protein.

CAML was identified as a cyclophilin-B-binding protein that elevates intracellular calcium and activates NF-AT signaling in T cells.

"causing an influx of calcium"

PMID:12919676

CAML is required for efficient EGF receptor recycling.

CAML-deficient cells have defective recycling of internalized EGFR to the plasma membrane.

"recycling of"

PMID:15451437

Immediate early gene X-1 interacts with proteins that modulate apoptosis.

PMID:16243292

Fibrocystin interacts with CAML, a protein involved in Ca2+ signaling.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:20553626

RNF122: a novel ubiquitin ligase associated with calcium-modulating cyclophilin ligand.

CAML binds and stabilizes the RING E3 ligase RNF122 (CAML is not an RNF122 substrate).

"it stabilizes RNF122"

PMID:22046132

The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.

PMID:23041287

Molecular machinery for insertion of tail-anchored membrane proteins into the endoplasmic reticulum membrane in mammalian cells.

CAML is the mammal-specific TRC40 receptor that, with WRB, mediates insertion of tail-anchored proteins into the ER membrane.

"We identify calcium-modulating cyclophilin ligand (CAML) as a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA proteins, and show that CAML mediates membrane insertion of TA proteins."

PMID:24658140

The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:27226539

Tail-anchored Protein Insertion in Mammals: FUNCTION AND RECIPROCAL INTERACTIONS OF THE TWO SUBUNITS OF THE TRC40 RECEPTOR.

In vitro reconstitution shows CAML and WRB together are sufficient to confer tail-anchored protein insertion competence to liposomes.

"in vitro synthesized CAML and WRB together were sufficient to confer insertion competence to liposomes"

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:31417168

The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER.

CAML is integrated into the ER membrane with three C-terminal transmembrane segments, dependent on WRB for correct topology.

"is inserted into the ER membrane with three transmembrane segments (TMs) in its C-terminal region"

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:32187542

Differential Modes of Orphan Subunit Recognition for the WRB/CAML Complex.

WRB and CAML reciprocally regulate each other's folding/stability within the insertase.

"When present, WRB can correct the topology of CAML both in vitro and in cells."

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32910895

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.

Cryo-EM of human WRB/CAML/TRC40 defines the GET insertase that inserts tail-anchored proteins into the ER membrane.

"mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/CAMLG/CAMLG-uniprot.txt

CAMLG UniProtKB record (P49069)

file:human/CAMLG/CAMLG-notes.md

Manual CAMLG curation notes

Suggested Experiments

Experiment: Perform proteome-wide profiling of tail-anchored protein levels/localization in CAMLG-knockout versus rescued cells, and reconstitute insertion of candidate clients in defined proteoliposomes containing WRB/CAML/TRC40.

Hypothesis: CAML is required for biogenesis of a defined repertoire of tail-anchored membrane proteins whose loss explains its physiological and disease phenotypes.

Type: tail-anchored protein biogenesis profiling and reconstitution

Experiment: Quantify N- and O-glycosylation and membrane-trafficking marker localization in CAMLG-patient-derived or knockout cells, correlating defects with abundance of specific tail-anchored SNAREs and trafficking factors.

Hypothesis: The CDG2Z glycosylation defect results from impaired insertion of tail-anchored components of the glycosylation/trafficking machinery rather than a direct glycosylation role for CAML.

Type: glycomics with membrane trafficking analysis

Deep Research

Falcon

(CAMLG-deep-research-falcon.md)

Comprehensive Research Report: CAMLG (Calcium Modulating Cyclophilin Ligand) Falcon

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: CAMLG (Calcium Modulating Cyclophilin Ligand)

Gene: CAMLG
UniProt ID: P49069
Organism: Homo sapiens
Protein Name: Guided entry of tail-anchored proteins factor CAMLG (also known as CAML, GET2)
Key Domains: Get2_like domain

1. Overview and Gene Identity Verification

CAMLG encodes an integral membrane protein known as calcium-modulating cyclophilin ligand (CAML), which serves as the GET2/CAML component of the transmembrane recognition complex (TRC) pathway in mammals (wilson2022camlgcdganovel pages 1-2, mcdowell2020structuralbasisof pages 1-3). The gene identity matches UniProt P49069, confirming research on the correct protein. CAMLG is also referred to as GET2 in comparative studies with yeast, where the homologous protein is encoded by the GET2 gene (mcdowell2020structuralbasisof pages 1-3, asseck2021endoplasmicreticulummembrane pages 1-2).

2. Primary Molecular Function

2.1 Role as a Membrane Insertase

CAMLG functions as an essential component of the GET/TRC pathway, which mediates the post-translational targeting and insertion of tail-anchored (TA) proteins into the endoplasmic reticulum (ER) membrane (wilson2022camlgcdganovel pages 1-2, zhang2025tailanchoredprotein pages 1-2, farkas2021captureanddelivery pages 1-3). TA proteins are defined as single-pass membrane proteins with a single C-terminal transmembrane domain (TMD) and lack an N-terminal signal peptide, necessitating their post-translational insertion after translation termination (farkas2021captureanddelivery pages 1-3, mcdowell2020structuralbasisof pages 1-3).

2.2 Molecular Mechanism

CAMLG forms a heteromeric receptor complex with WRB (tryptophan-rich basic protein, also known as GET1 in yeast) in the ER membrane (wilson2022camlgcdganovel pages 1-2, mcdowell2020structuralbasisof pages 1-3). This receptor complex receives TA protein substrates from the cytosolic ATPase TRC40 (also called GET3 in yeast or ASNA1), which chaperones the TA proteins through the cytoplasm by shielding their hydrophobic transmembrane domains within a dedicated hydrophobic groove (farkas2021captureanddelivery pages 1-3, mcdowell2020structuralbasisof pages 1-3).

The CAMLG/WRB insertase complex adopts a heterotetramer stoichiometry (2:2:2 ratio of WRB:CAMLG:TRC40) upon binding to TRC40 loaded with substrate TA proteins (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6). This heterotetramerization is induced by TRC40 binding and is essential for efficient TA protein insertion (mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6). Native mass spectrometry and cryo-electron microscopy analyses confirmed this assembly in both mammalian and yeast systems (mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6).

2.3 Substrate Specificity

CAMLG demonstrates specificity for TA proteins with relatively long, hydrophobic C-terminal transmembrane domains (farkas2021captureanddelivery pages 4-5, jung2023quantitativemassspectrometry pages 1-3). Substrates with less hydrophobic TMDs are poor clients for the TRC40/CAMLG pathway and often utilize alternative insertion mechanisms such as the ER membrane protein complex (EMC) (farkas2021captureanddelivery pages 4-5). The substrate spectrum includes predominantly membrane proteins with C-terminal targeting signals, in contrast to the signal recognition particle (SRP) pathway which handles proteins with N-terminal signal peptides or transmembrane helices (jung2023quantitativemassspectrometry pages 1-3).

Key substrates identified through proteomic and genetic approaches include SNARE proteins involved in vesicular trafficking, such as syntaxin-5 (STX5), BET1L, SEC22B, VAMP7, VTI1A, and STX6, as well as SNARE-interacting proteins like VAPA and VAPB (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6). A comprehensive table of CAMLG substrates and their functions is provided below.

Substrate/Client Protein Name	Function/Role	Evidence Type	Citation
STX5 (syntaxin-5; STX5L/STX5S)	Golgi/ER SNARE required for Golgi trafficking and retrograde transport; a tail-anchored (TA) membrane protein particularly sensitive to CAMLG/TRC pathway deficiency	Patient fibroblasts and CAMLG-knockdown HeLa cells showed STX5 mislocalization from membrane/Golgi to cytoplasmic fractions; mouse CAML-deficiency studies identified syntaxin-5 as a key TA protein affected by loss of TA insertion machinery	(wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6, zhang2025tailanchoredprotein pages 2-4)
BET1L	v-SNARE involved in Golgi SNARE complex assembly and vesicular trafficking; TA membrane protein	Reduced steady-state levels in CAMLG-CDG fibroblasts and CAMLG-knockdown HeLa cells; interpreted as a consistent marker of TRC dysfunction affecting Golgi SNARE machinery	(wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6)
SEC22B	SNARE involved in vesicle trafficking between ER and Golgi; cited as an ER-targeted TA protein of the secretory pathway	Review/database-style synthesis of TRC pathway clients and TA proteins of the secretory pathway; listed among vesicular transport components relying on ER TA insertion machinery	(wilson2022camlgcdganovel pages 1-2, tirincsi2022proteomicsidentifiessubstrates pages 1-2, jung2023quantitativemassspectrometry pages 1-3)
VAMP7	Vesicle-associated SNARE involved in membrane fusion and intracellular trafficking; cited as an ER-targeted TA protein	Review/database-style synthesis identifying VAMP7 among TA proteins of the secretory pathway that depend on TRC/GET-mediated ER insertion	(wilson2022camlgcdganovel pages 1-2, tirincsi2022proteomicsidentifiessubstrates pages 1-2, jung2023quantitativemassspectrometry pages 1-3)
VTI1A	SNARE/interactor in vesicular trafficking between Golgi/ER compartments; TA membrane protein	Cited in disease study as an example of ER-targeted TA proteins involved in conventional trafficking and likely affected by TRC pathway dysfunction	(wilson2022camlgcdganovel pages 1-2)
STX6 (syntaxin-6)	Golgi/endosomal SNARE in vesicular targeting and fusion; TA membrane protein	Cited as an ER-targeted TA protein involved in vesicular trafficking in the context of CAMLG/TRC pathway function	(wilson2022camlgcdganovel pages 1-2)
VAPA	Vesicle-trafficking/SNARE-interacting membrane protein; TA membrane protein	Cited as an example of a TA client linked to ER/Golgi trafficking pathways supported by TRC machinery	(wilson2022camlgcdganovel pages 1-2)
VAPB	Vesicle-trafficking/SNARE-interacting membrane protein; TA membrane protein	Cited as an example of a TA client linked to ER/Golgi trafficking pathways supported by TRC machinery	(wilson2022camlgcdganovel pages 1-2)
CUX1	Protein later trafficked to the nuclear membrane; contains a TA membrane anchor	Mentioned as a TA protein later trafficked to nuclear membrane after ER insertion, illustrating breadth of CAMLG-dependent client destinations	(wilson2022camlgcdganovel pages 1-2)
EMD (emerin)	Inner nuclear membrane protein with TA targeting route through ER	Mentioned as a TA protein trafficked to nuclear membrane after ER insertion via TRC machinery	(wilson2022camlgcdganovel pages 1-2)
Sec61β / Sec61γ	Tail-anchored subunits of the Sec61 complex; components of ER protein translocation machinery	Used in reviews as canonical examples of secretory-pathway TA proteins targeted and inserted into the ER membrane via TRC/GET-type mechanisms	(mcdowell2020structuralbasisof pages 1-3, tirincsi2022proteomicsidentifiessubstrates pages 1-2)
ER/Golgi TA SNARE client class	Broad class including many vesicular trafficking factors; dominant functional client group for CAMLG	Proteomic evaluation concluded that TRC/GET clients are predominantly membrane proteins with central or C-terminal targeting signals, enriched for vesicular trafficking functions	(jung2023quantitativemassspectrometry pages 1-3)
TA proteins with hydrophobic C-terminal transmembrane domains	Core substrate class of CAMLG receptor complex; inserted post-translationally into ER membrane	Mechanistic/structural studies show CAMLG-WRB receives TRC40-bound substrates bearing a single C-terminal TMD; ER/Golgi TA proteins generally have relatively long, hydrophobic TMDs	(farkas2021captureanddelivery pages 1-3, mcdowell2020structuralbasisof pages 1-3, farkas2021captureanddelivery pages 4-5)
TA proteins with less hydrophobic TMDs	Poorer substrates for TRC/CAMLG; often use alternative pathways such as EMC	Review evidence notes less hydrophobic TMDs are poor substrates for Get3/TRC40 capture, defining CAMLG substrate specificity boundaries	(farkas2021captureanddelivery pages 4-5)
TA proteins with C-terminal location of the TMD (type IV membrane proteins)	Defining topology recognized by TRC/CAMLG pathway; N-terminus faces cytosol after insertion	Human ER-targeting reviews define TA proteins as single-pass proteins lacking cleavable signal peptide with the TMH at the extreme C-terminus, making them CAMLG/TRC clients	(tirincsi2022proteomicsidentifiessubstrates pages 1-2, jung2023quantitativemassspectrometry pages 1-3)

Table: This table summarizes specific and representative CAMLG/TRC pathway client proteins and substrate classes, emphasizing vesicular trafficking SNAREs and the biophysical features that define CAMLG substrate specificity. It is useful for linking CAMLG’s molecular role at the ER membrane to experimentally observed trafficking and glycosylation phenotypes.

3. Subcellular Localization

CAMLG is an integral membrane protein of the endoplasmic reticulum (wilson2022camlgcdganovel pages 1-2, zhang2025tailanchoredprotein pages 1-2). It localizes specifically to the ER membrane where it performs its function as a receptor for TA protein insertion (mcdowell2020structuralbasisof pages 1-3, asseck2021endoplasmicreticulummembrane pages 1-2). CAMLG carries out its essential role at the ER membrane interface, where it receives TA protein-loaded TRC40 from the cytosol and facilitates substrate insertion into the lipid bilayer (farkas2021captureanddelivery pages 1-3, mcdowell2020structuralbasisof pages 1-3).

The protein topology features three transmembrane domains (TMD1, TMD2, and TMD3) that traverse the ER membrane, with an N-terminal cytoplasmic domain facing the cytosol and C-terminal regions oriented toward the ER lumen (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6). This orientation allows CAMLG to interact with cytosolic TRC40 while facilitating substrate integration into the membrane (mcdowell2020structuralbasisof pages 1-3).

4. Structural Architecture

4.1 Domain Organization

Cryo-electron microscopy structures at 4.2 Å resolution have revealed the detailed architecture of the human CAMLG/WRB/TRC40 complex (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5). CAMLG contains three transmembrane domains that form a three-helical bundle, which interacts with the three-transmembrane-domain core of WRB (mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6). Notably, CAMLG TMD3 acts as a central linchpin within the complex, forming a long 55 Å helix tilted at 45° relative to the membrane normal and protruding into the cytoplasm (mcdowell2020structuralbasisof pages 5-6).

4.2 Functional Elements

A key structural feature is the cytoplasmic helix α30 in CAMLG, which forms a "gating" interaction with TRC40/GET3 (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5). This helix is functionally important for guiding TA substrates toward the membrane for insertion (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5). The CAMLG/WRB complex also features a conserved hydrophilic groove within the membrane that likely facilitates passage of the TA substrate through the lipid bilayer (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5).

4.3 Evolutionary Conservation

Despite low sequence homology, CAMLG orthologs across eukaryotes (yeast Get2, plant G1IP, mammalian CAML) show conserved function with structural features rather than sequence conservation determining functionality (asseck2021endoplasmicreticulummembrane pages 1-2, kizmaz2023membraneinsertasesat pages 1-2, asseck2021endoplasmicreticulummembrane pages 2-3). Structural comparison reveals that CAMLG belongs to the Oxa1 superfamily of membrane insertases, sharing architectural similarities with bacterial YidC and the EMC3/EMC6 subcomplex of the ER membrane protein complex, suggesting an evolutionarily conserved insertion mechanism (mcdowell2020structuralbasisof pages 1-3, kizmaz2023membraneinsertasesat pages 1-2, mcdowell2020structuralbasisof pages 4-5).

5. Biochemical Pathway and Biological Processes

5.1 The GET/TRC Pathway

CAMLG functions as the terminal receptor in the GET/TRC pathway for post-translational TA protein targeting and membrane insertion (wilson2022camlgcdganovel pages 1-2, farkas2021captureanddelivery pages 1-3, tirincsi2022proteomicsidentifiessubstrates pages 1-2). The complete pathway operates through the following steps:

Ribosome-associated capture: Nascent TA proteins emerging from ribosomes are captured by the pretargeting complex composed of SGTA (also called Sgt2 in yeast) along with the BAG6 complex (BAG6, UBL4A, TRC35 in mammals; Get4-Get5 in yeast) (farkas2021captureanddelivery pages 1-3, farkas2021captureanddelivery pages 3-4, farkas2021captureanddelivery pages 4-5). Recent evidence indicates that Get4-Get5 associates with ribosomes and enhances TA protein capture by recruiting Sgt2 to the ribosome exit tunnel (farkas2021captureanddelivery pages 3-4, farkas2021captureanddelivery pages 4-5).
Transfer to TRC40: The TA protein is transferred from SGTA to the ATP-bound form of TRC40/GET3, which shields the hydrophobic TMD within a dedicated hydrophobic groove (farkas2021captureanddelivery pages 1-3, farkas2021captureanddelivery pages 4-5). This handover is facilitated by the pretargeting complex and involves ATP hydrolysis (farkas2021captureanddelivery pages 1-3).
ER membrane targeting: The TRC40-TA protein complex is delivered to the ER membrane where it initially binds to CAMLG (Get2) through positively charged residues in CAMLG's cytoplasmic N-terminus (farkas2021captureanddelivery pages 1-3, mcdowell2020structuralbasisof pages 1-3).
Membrane insertion: Subsequent binding of WRB (Get1) to the complex triggers ADP release from TRC40 and conformational changes that promote TA substrate release and insertion into the ER membrane (farkas2021captureanddelivery pages 1-3, mcdowell2020structuralbasisof pages 1-3). The heterotetramer architecture formed by two copies each of CAMLG and WRB provides the insertion machinery (mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6).

5.2 Key Biological Processes

Vesicular Trafficking: The most prominent biological function of CAMLG is maintaining proper vesicular trafficking between the ER and Golgi compartments through insertion of essential SNARE proteins (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6). Many SNARE proteins involved in vesicle fusion, including syntaxin-5 (a v-SNARE critical for retrograde Golgi-to-ER trafficking), are TA proteins that require CAMLG for proper membrane insertion (wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6).

Protein Glycosylation: Proper function of CAMLG is essential for maintaining normal protein glycosylation patterns (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3, wilson2022camlgcdganovel pages 5-6). Deficiency in CAMLG leads to combined N-linked and O-linked glycosylation defects, manifesting as a congenital disorder of glycosylation (CAMLG-CDG) (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3). These glycosylation defects arise from impaired Golgi trafficking machinery due to mislocalization of critical SNARE proteins (wilson2022camlgcdganovel pages 2-3, wilson2022camlgcdganovel pages 5-6).

Quality Control: CAMLG participates in protein quality control by working with the BAG6 complex, which has dual functions in both TA protein targeting and ubiquitination of aberrant proteins (farkas2021captureanddelivery pages 3-4, farkas2021captureanddelivery pages 4-5). The interplay between SGTA and BAG6 determines whether TA proteins are routed for productive insertion or degradation (farkas2021captureanddelivery pages 4-5).

6. Experimental Evidence

6.1 Structural Studies

High-resolution cryo-electron microscopy studies (McDowell et al., 2020) provided atomic-level insights into the CAMLG/WRB/TRC40 complex, revealing the heterotetramer architecture at 4.2 Å resolution (mcdowell2020structuralbasisof pages 1-3, mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6). Native mass spectrometry confirmed the 2:2:2 stoichiometry of WRB:CAMLG:TRC40 complexes and demonstrated that heterotetramerization occurs upon TRC40 binding (mcdowell2020structuralbasisof pages 4-5, mcdowell2020structuralbasisof pages 5-6). Blue native PAGE analysis of yeast microsomes confirmed that endogenous Get3 associates with Get1/Get2 heterotetramers in their native membrane environment (mcdowell2020structuralbasisof pages 5-6).

6.2 Disease Model Studies

Patient-derived fibroblasts carrying a homozygous splice variant (c.633+4A>G) in CAMLG that leads to exon 2 skipping and loss of functional CAML protein provided direct evidence for CAMLG function in humans (Wilson et al., 2022) (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3). These cells exhibited:

Mislocalization of syntaxin-5 (STX5) from membrane to cytoplasmic fractions (wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6)
Significantly reduced steady-state levels of BET1L (wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6)
Combined type II N-linked and O-linked glycosylation defects in serum proteins (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3, wilson2022camlgcdganovel pages 5-6)
Abnormal sialylation patterns detected by peanut agglutinin (PNA) lectin staining (wilson2022camlgcdganovel pages 5-6)

The patient presented with severe neurological phenotypes including psychomotor disability, hypotonia, seizures, and structural brain abnormalities, confirming TRC pathway defects as congenital disorders of glycosylation (CAMLG-CDG) (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3).

6.3 Mouse Model Studies

Mouse models with reduced CAML expression (Zhang et al., 2025) demonstrated that CAML is essential for neuromuscular function (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4). Pseudo-hypomorphic mice with globally reduced CAML levels developed hindlimb weakness progressing to paralysis, with loss of motor neuron cell bodies in spinal cord sections (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4). Conditional knockout of CAML specifically in neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating a cell-autonomous role for CAML in motor neuron survival (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4).

Cellular analysis of CAML-deficient cells revealed:
- Perturbed intracellular trafficking with aberrant procathepsin D release (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4)
- Defective retention of CD222 in the trans-Golgi network (zhang2025tailanchoredprotein pages 2-4)
- Reduced levels and mislocalization of syntaxin-5 (zhang2025tailanchoredprotein pages 2-4)
- Dysfunctional lysosomes and abnormal protein glycosylation (zhang2025tailanchoredprotein pages 2-4)

Identical phenotypes were observed in mice lacking ASNA1 (TRC40) in neurons, confirming that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4).

6.4 Proteomic Studies

Quantitative mass spectrometry approaches combined with differential protein abundance analysis after CAMLG depletion (Jung and Zimmermann, 2023) systematically characterized the client spectrum of the TRC pathway (jung2023quantitativemassspectrometry pages 1-3). These studies confirmed that TRC clients are predominantly membrane proteins with central or C-terminal targeting signals, enriched for vesicular trafficking functions (jung2023quantitativemassspectrometry pages 1-3). The proteomic data validated syntaxin-5 as a particularly sensitive substrate and identified additional TA clients affected by CAMLG/TRC pathway disruption (jung2023quantitativemassspectrometry pages 1-3).

6.5 Biochemical and Cell Biological Studies

Immunofluorescence studies consistently demonstrate that loss of CAMLG function results in mislocalization of SNARE proteins, particularly syntaxin-5, from Golgi/membrane compartments to the cytoplasm (wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6). This mislocalization serves as a reliable cellular marker of TRC dysfunction (wilson2022camlgcdganovel pages 2-3, wilson2022camlgcdganovel pages 5-6). Crude cell fractionation experiments confirmed the redistribution of STX5 isoforms (STX5L and STX5S) to cytoplasmic fractions in CAMLG-deficient cells (wilson2022camlgcdganovel pages 4-5, wilson2022camlgcdganovel pages 5-6).

Functional complementation studies in yeast demonstrated that plant and mammalian GET pathway components can rescue yeast GET receptor mutants, but only when appropriate receptor pairs are co-expressed, confirming the requirement for heteromeric WRB/CAMLG complex formation (asseck2021endoplasmicreticulummembrane pages 1-2, asseck2021endoplasmicreticulummembrane pages 2-3).

7. Recent Developments (2023-2025)

Recent studies have expanded our understanding of CAMLG function and its broader implications:

7.1 Rules of Engagement for ER Membrane Protein Biogenesis

Zimmermann (2025) provided a comprehensive analysis of how different ER targeting pathways, including the TRC pathway involving CAMLG, select their client proteins based on features of topogenic sequences (jung2023quantitativemassspectrometry pages 1-3). The study confirmed that the TRC pathway preferentially handles membrane proteins with more central or C-terminal transmembrane domains, contrasting with the SRP pathway's preference for N-terminal signals (jung2023quantitativemassspectrometry pages 1-3).

7.2 Neuromuscular Disease Implications

The Zhang et al. (2025) study establishing the link between CAML/TRC40 and neuromuscular function in mice highlighted motor neuron survival as a key physiological role for the TA protein insertion machinery (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4). This finding has implications for understanding the pathogenesis of neuromuscular diseases in humans and suggests that disruptions in TA protein biogenesis may contribute to motor neuron degeneration (zhang2025tailanchoredprotein pages 1-2, zhang2025tailanchoredprotein pages 2-4).

7.3 Membrane Insertase Mechanisms

Kizmaz and Herrmann (2023) provided a comprehensive overview of membrane insertases, placing CAMLG within the context of the Oxa1 family of insertases that facilitate integration of proteins with α-helical transmembrane domains (kizmaz2023membraneinsertasesat pages 1-2). This review highlighted how CAMLG serves as a catalytically active core subunit in the GET complex alongside related Oxa1-type insertases in the EMC and GEL complexes in the ER (kizmaz2023membraneinsertasesat pages 1-2).

8. Clinical Relevance

CAMLG deficiency causes CAMLG-CDG (CAMLG-congenital disorder of glycosylation), a novel genetic disorder characterized by combined N- and O-linked glycosylation defects resulting from membrane trafficking dysfunction (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3). Clinical manifestations include:

Severe developmental delay and intellectual disability (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3)
Hypotonia and limb contractures (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3)
Seizures (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3)
Structural brain abnormalities including corpus callosum thinning, brain stem atrophy, and hypomyelination (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3)
Biochemical abnormalities in serum transferrin and apolipoprotein C-III glycoforms (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3, wilson2022camlgcdganovel pages 5-6)

CAMLG-CDG represents the third disorder caused by pathogenic variants in TRC pathway components, following GET3 (ASNA1) and GET4 deficiencies, establishing TRC pathway disorders as a novel group of congenital disorders of glycosylation (wilson2022camlgcdganovel pages 1-2, wilson2022camlgcdganovel pages 2-3).

9. Summary

CAMLG encodes an essential ER membrane receptor protein that, together with WRB, forms the terminal insertase complex of the GET/TRC pathway for tail-anchored protein biogenesis. The protein facilitates post-translational insertion of TA proteins with hydrophobic C-terminal transmembrane domains into the ER membrane, with particular importance for SNARE proteins involved in vesicular trafficking between the ER and Golgi. Structural studies reveal that CAMLG forms a heterotetramer with WRB upon binding to TRC40-loaded substrates, utilizing a conserved hydrophilic groove and gating helix to mediate substrate insertion. Deficiency in CAMLG causes severe neurological disease in humans and mice, primarily through disruption of membrane trafficking and protein glycosylation, establishing CAMLG as essential for normal development and cellular homeostasis.

Key References

McDowell, M.A. et al. (2020). Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex. Molecular Cell 80:72-86. doi:10.1016/j.molcel.2020.08.012
Wilson, M.P. et al. (2022). CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking. Human Molecular Genetics 31:2571-2581. doi:10.1093/hmg/ddac055
Zhang, Y. et al. (2025). Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. PLOS Genetics 21:e1011547. doi:10.1371/journal.pgen.1011547
Jung, M. & Zimmermann, R. (2023). Quantitative Mass Spectrometry Characterizes Client Spectra of Components for Targeting of Membrane Proteins to the Human ER. International Journal of Molecular Sciences 24:14166. doi:10.3390/ijms241814166
Farkas, Á. & Bohnsack, K.E. (2021). Capture and delivery of tail-anchored proteins to the endoplasmic reticulum. The Journal of Cell Biology 220:e202105004. doi:10.1083/jcb.202105004
Asseck, L.Y. et al. (2021). Endoplasmic reticulum membrane receptors of the GET pathway are conserved throughout eukaryotes. Proceedings of the National Academy of Sciences 118:e2017636118. doi:10.1073/pnas.2017636118
Kizmaz, B. & Herrmann, J.M. (2023). Membrane insertases at a glance. Journal of Cell Science 136:jcs261219. doi:10.1242/jcs.261219

References

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(farkas2021captureanddelivery pages 3-4): Ákos Farkas and Katherine E. Bohnsack. Capture and delivery of tail-anchored proteins to the endoplasmic reticulum. The Journal of Cell Biology, Jul 2021. URL: https://doi.org/10.1083/jcb.202105004, doi:10.1083/jcb.202105004. This article has 49 citations.
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📚 Additional Documentation

Notes

(CAMLG-notes.md)

CAMLG (P49069) curation notes

Identity

HGNC: CAMLG; aka CAML (calcium-modulating cyclophilin ligand), GET2.
UniProt RecName: "Guided entry of tail-anchored proteins factor CAMLG".
Multi-pass ER membrane protein: large cytoplasmic N-terminal region (1-189, disordered N-terminus), then three C-terminal TM helices (190-207, 213-231, 270-288). Topology established in PMID:31417168.
Disease: Congenital disorder of glycosylation 2Z (CDG2Z, MIM:620201), autosomal recessive, neurological phenotype; caused by defective membrane trafficking (PMID:35262690 — not cached).

Core function: GET/TRC insertase receptor for tail-anchored (TA) proteins

CAML, together with WRB/GET1, forms the mammalian ER membrane receptor for the cytosolic ATPase TRC40/GET3, which delivers newly synthesized tail-anchored membrane proteins for post-translational insertion into the ER membrane. CAML is the mammal-specific subunit (not homologous to yeast Get2); WRB is the Get1 orthologue.

PMID:23041287
PMID:23041287
PMID:27226539
PMID:27226539
PMID:32910895 — structural basis: WRB/CAML/TRC40 heterotetramer, PI-stabilized; disulfide bond 208-284 (UniProt FT DISULFID).
PMID:32187542

Reactome: R-HSA-9609523 "Insertion of tail-anchored proteins into the endoplasmic reticulum membrane".

GET complex membership and reciprocal stability with WRB

CAML and WRB depend on each other for stability/correct topology.
- PMID:32187542
- PMID:31417168
- GO terms: GET complex (GO:0043529) part_of — well supported (IDA PMID:32910895, IPI PMID:23041287). Protein stabilization (GO:0050821) is supported in the WRB/CAML context (PMID:32187542) but note PMID:20553626 also annotated stabilization in the unrelated RNF122 context.

Secondary / historical functions

Calcium signaling (original discovery)

CAML was originally cloned as a cyclophilin-B-binding protein that induces calcium influx in T cells and activates NF-AT/IL-2 transcription. This is the historical basis of the "defense response" (GO:0006952) and "signal transduction" (GO:0007165) TAS annotations from PMID:7522304. Plausible but largely supplanted by the well-established GET insertase role; treat as non-core/contextual.
- PMID:7522304

B cell homeostasis

By-similarity/ISS: "Essential for the survival of peripheral follicular B cells" (UniProt). Mouse phenotype; CAML interacts with TACI/TNFRSF13B (PMID:9311921 — not cached). Non-core for the human gene's molecular function.

EGFR recycling

CAML-deficient cells have defective EGFR recycling; CAML associates with the EGFR kinase domain ligand-dependently (PMID:12919676). This is the basis of Ensembl IEA "receptor recycling" and "epidermal growth factor receptor signaling pathway" terms (not in the current existing_annotations list except via interactome IPI). Context-dependent; potentially confounded by the general role of CAML in membrane protein biogenesis.

The negative regulation of (protein) ubiquitination / proteasomal catabolism / protein stabilization and ubiquitin-protein-ligase-binding annotations all derive from one yeast-two-hybrid + co-IP study of the RING E3 RNF122, in which CAML stabilizes RNF122 (and is not its substrate). These are narrow, single-study, context-specific findings, not the core GET function.
- PMID:20553626
- PMID:20553626

Over-annotations / non-informative

GO:0005515 protein binding (IPI) appears ~12 times from interactome/Y2H/MaMTH/coronavirus-host studies (PMID:15451437, 16243292, 22046132, 24658140, 25416956, 28514442, 31980649, 32296183, 33961781, 40205054, 31417168, 32187542). Bare "protein binding" is uninformative; meaningful interactions (WRB, GET3, TACI, RNF122, EGFR) are captured by specific terms or noted in core function.
GO:0016020 membrane (HDA, PMID:19946888) — generic; subsumed by ER membrane terms.
GO:0005737 cytoplasm (IDA, PMID:20553626) — CAML has a large cytoplasmic domain, but the protein is an integral ER membrane protein; ER membrane terms are the correct localization.

Localization

Well supported: ER membrane / ER (multiple EXP/IDA: PMID:23041287, PMID:31417168, PMID:12919676). Core.

Summary of action plan

CORE: GET complex (GO:0043529) part_of; tail-anchored membrane protein insertion into ER membrane (GO:0071816); protein insertion into ER membrane (GO:0045048); ER membrane (GO:0005789); endoplasmic reticulum (GO:0005783).
NON-CORE (real but secondary/contextual): protein stabilization (GO:0050821, WRB/CAML context); B cell homeostasis (GO:0001782); defense response (GO:0006952); signal transduction (GO:0007165).
NON-CORE single-study (RNF122): negative regulation of protein ubiquitination (GO:0031397), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), ubiquitin protein ligase binding (GO:0031625).
OVER-ANNOTATED: bare protein binding (all IPI), generic membrane, cytoplasm.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/CAMLG/CAMLG-deep-research-falcon.md,
25 citations). It strongly corroborates the GET/TRC insertase-receptor core above and
adds substrate-specificity and disease-mechanism detail; no change to the core call.

Core confirmed. CAMLG (with WRB) is the ER receptor for TRC40/GET3 that
inserts tail-anchored (type-IV, C-terminal single-TMD) proteins post-
translationally; substrate selectivity is for relatively long, hydrophobic
C-terminal TMDs (less-hydrophobic TA proteins default to the EMC pathway).
Supports the GET-complex (GO:0043529) and TA-insertion calls.
Specific TA-protein clients (Wilson 2022; Tirincsi 2022; Jung 2023). The
client spectrum is enriched for trafficking SNAREs — STX5, BET1L, SEC22B,
VAMP7, VTI1A (itself a PROTEOSTASIS gene in this batch), STX6, VAPA/VAPB —
plus Sec61β/γ and nuclear-membrane TA proteins (emerin/EMD, CUX1). Useful
has-input/affected-client context for the insertase function.
CDG2Z mechanism made concrete. CAMLG-CDG (congenital disorder of
glycosylation) arises because loss of TA insertion mislocalizes Golgi SNAREs,
especially STX5 and BET1L (membrane→cytosol), disrupting Golgi trafficking and
causing combined N-/O-glycosylation defects (Wilson 2022). This is the
mechanistic basis for the CDG2Z disease noted above — links the ER insertase MF
to the downstream glycosylation phenotype.
Quality-control interplay. CAMLG/TRC works with SGTA and the BAG6
complex, which route TA proteins between productive insertion and
ubiquitin-mediated degradation (Farkas 2021) — supports the proteostasis (PN)
framing and the protein-stabilization context.

Net: no change to calls — CAMLG is the mammal-specific ER GET-pathway insertase
receptor subunit (with WRB) for tail-anchored proteins; the new client/disease
detail strengthens that core and its proteostasis relevance.

Pn Notes

(CAMLG-pn-notes.md)

CAMLG PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P49069
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/CAMLG/CAMLG-ai-review.yaml
AIGR review HTML: present - genes/human/CAMLG/CAMLG-ai-review.html
Gene notes: present - genes/human/CAMLG/CAMLG-notes.md
GOA TSV: present - genes/human/CAMLG/CAMLG-goa.tsv
UniProt record: present - genes/human/CAMLG/CAMLG-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CAMLG.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CAMLG.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: CAMLG (CAML; calcium-modulating cyclophilin ligand; also GET2) is an integral endoplasmic reticulum membrane protein with a large cytoplasmic N-terminal region and three C-terminal transmembrane helices. Together with WRB (GET1), it constitutes the mammalian ER membrane receptor for the cytosolic ATPase TRC40/GET3, forming the GET (guided entry of tail-anchored proteins) insertase complex. This complex captures newly synthesized tail-anchored membrane proteins from TRC40/GET3 in the cytosol and mediates their post-translational insertion into the ER membrane. CAML is the mammal-specific subunit (not homologous to yeast Get2) and forms a heterotetramer with WRB stabilized by phosphatidylinositol binding; CAML and WRB are mutually dependent for correct membrane integration and stability. CAML was originally identified as a cyclophilin-B-binding protein that elevates intracellular calcium and activates NF-AT signaling in T cells, and it has additional reported roles in B cell survival, EGFR recycling, and stabilization of the E3 ligase RNF122. Biallelic variants cause an autosomal recessive congenital disorder of glycosylation (CDG2Z) characterized by a neurological phenotype and defective membrane trafficking.
Existing/core annotation action counts: ACCEPT: 14; KEEP_AS_NON_CORE: 7; MARK_AS_OVER_ANNOTATED: 16

PN Consistency Summary

Consistency: Partial conflict. The GET-pathway row is fully consistent: review, notes and deep research all establish CAMLG/CAML (GET2) as the mammal-specific subunit of the WRB/CAML/TRC40 GET insertase for tail-anchored proteins (PMID:23041287, 27226539, 32910895, 31417168). But PN row 1 classifies CAMLG as a cyclophilin-type peptidyl-prolyl isomerase projecting GO:0003755 (PPIase activity). The review, notes and UniProt give NO evidence CAML has PPIase activity — it was named for binding cyclophilin B (PMID:7522304), not for being one. PPIase projection to this gene is a misclassification.
PN story / NEW pressure: GET-targeting role (GO:0006620, verified real) is correct and is NOT in current GOA as that exact term — review instead carries the better, more specific GO:0071816 (TA insertion into ER) and GO:0045048. So the GET process is already captured at gene level by a narrower term. GO:0003755 PPIase activity is an over-reach (no enzymatic evidence). Conclusion: GET row already captured (more specifically); PPIase row over-reaches.
Evidence alignment: PN row 1 cites no references; PN row 2 cites none. Review evidence (GET insertase PMIDs) does not overlap any PPIase literature, reinforcing the misclassification.
Verdict: GET-pathway placement sound and already captured by a more specific gene-level term; PPIase classification is a misassignment — CAML binds cyclophilin B but is not a PPIase. Recommended edits: [MAP] flag CAMLG as a non-member of the PN "Peptidyl-prolyl isomerases / Cyclophilin type" node, or block GO:0003755 projection onto P49069 (binds cyclophilin, no isomerase activity).

Full Consistency Review

UniProt: P49069 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE
PN placement: two rows — ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|Cyclophilin type and ER proteostasis|Protein transport|GET pathway component ; PN-node mapping: GET group → mapped/ok_for_propagation GO:0006620 (post-translational targeting to ER membrane); Protein-transport class → mapped GO:0015031 protein transport; PPIase group/type → mapped GO:0003755 PPIase activity.
Consistency: Partial conflict. The GET-pathway row is fully consistent: review, notes and deep research all establish CAMLG/CAML (GET2) as the mammal-specific subunit of the WRB/CAML/TRC40 GET insertase for tail-anchored proteins (PMID:23041287, 27226539, 32910895, 31417168). But PN row 1 classifies CAMLG as a cyclophilin-type peptidyl-prolyl isomerase projecting GO:0003755 (PPIase activity). The review, notes and UniProt give NO evidence CAML has PPIase activity — it was named for binding cyclophilin B (PMID:7522304), not for being one. PPIase projection to this gene is a misclassification.
PN story / NEW pressure: GET-targeting role (GO:0006620, verified real) is correct and is NOT in current GOA as that exact term — review instead carries the better, more specific GO:0071816 (TA insertion into ER) and GO:0045048. So the GET process is already captured at gene level by a narrower term. GO:0003755 PPIase activity is an over-reach (no enzymatic evidence). Conclusion: GET row already captured (more specifically); PPIase row over-reaches.
Mapping strategy: GET group mapping (GO:0006620, scope ok) is defensible but broader than the review's GO:0071816; treat as group-level only, do not project onto CAMLG (gene already has the specific term). The PPIase group/type mapping should NOT project onto CAMLG.
Evidence alignment: PN row 1 cites no references; PN row 2 cites none. Review evidence (GET insertase PMIDs) does not overlap any PPIase literature, reinforcing the misclassification.
Verdict: GET-pathway placement sound and already captured by a more specific gene-level term; PPIase classification is a misassignment — CAML binds cyclophilin B but is not a PPIase. Recommended edits: [MAP] flag CAMLG as a non-member of the PN "Peptidyl-prolyl isomerases / Cyclophilin type" node, or block GO:0003755 projection onto P49069 (binds cyclophilin, no isomerase activity).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/CAMLG/CAMLG-ai-review.yaml
PN workbook rows: 2

PN row 1: ER proteostasis | Folding enzyme | Peptidyl-prolyl isomerases | Cyclophilin type

UniProt: P49069
In branches: ER
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|Cyclophilin type
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0003755 peptidyl-prolyl cis-trans isomerase activity]
  rationale: This PN type denotes ER cyclophilin-family PPIases. The matching GO molecular function is appropriate for propagation.
- [group] ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0003755 peptidyl-prolyl cis-trans isomerase activity]
  rationale: This PN group is the ER peptidyl-prolyl isomerase family. The GO PPIase activity term is the appropriate propagation target for this folding enzyme bucket.
- [class] ER proteostasis|Folding enzyme
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: ER proteostasis | Protein transport | GET pathway component

UniProt: P49069
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Protein transport|GET pathway component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane]
  rationale: The PN GET-pathway group covers machinery for post-translational delivery of tail-anchored membrane proteins to the ER. GO does not model the GET pathway directly in the local cache, and the closest supported process term is post-translational targeting to the ER membrane.
- [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 (4)

GO:0003755 peptidyl-prolyl cis-trans isomerase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases
GO:0003755 peptidyl-prolyl cis-trans isomerase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|Cyclophilin type
GO:0015031 protein transport | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport
GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Protein transport|GET pathway 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: P49069
gene_symbol: CAMLG
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CAMLG (CAML; calcium-modulating cyclophilin ligand; also GET2) is an
  integral endoplasmic reticulum membrane protein with a large cytoplasmic N-terminal
  region and three C-terminal transmembrane helices. Together with WRB (GET1), it constitutes
  the mammalian ER membrane receptor for the cytosolic ATPase TRC40/GET3, forming the
  GET (guided entry of tail-anchored proteins) insertase complex. This complex captures
  newly synthesized tail-anchored membrane proteins from TRC40/GET3 in the cytosol
  and mediates their post-translational insertion into the ER membrane. CAML is the
  mammal-specific subunit (not homologous to yeast Get2) and forms a heterotetramer
  with WRB stabilized by phosphatidylinositol binding; CAML and WRB are mutually dependent
  for correct membrane integration and stability. CAML was originally identified as
  a cyclophilin-B-binding protein that elevates intracellular calcium and activates
  NF-AT signaling in T cells, and it has additional reported roles in B cell survival,
  EGFR recycling, and stabilization of the E3 ligase RNF122. Biallelic variants cause
  an autosomal recessive congenital disorder of glycosylation (CDG2Z) characterized
  by a neurological phenotype and defective membrane trafficking.'
existing_annotations:
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: CAML is a core component of the GET insertase complex (with WRB/GET1 and
      TRC40/GET3); this is the central, well-supported localization.
    action: ACCEPT
    reason: Direct experimental and structural evidence establish CAML as a subunit
      of the GET complex; phylogenetic transfer is correct.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: We identify calcium-modulating cyclophilin ligand (CAML) as
        a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized
        TA proteins, and show that CAML mediates membrane insertion of TA proteins.
      reference_section_type: ABSTRACT
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This is the core biological process for CAML - post-translational insertion
      of tail-anchored membrane proteins into the ER membrane.
    action: ACCEPT
    reason: Directly supported by reconstitution and depletion studies; the most specific
      and accurate process term for CAML.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: We identify calcium-modulating cyclophilin ligand (CAML) as
        a mammal-specific receptor for TRC40, an ATPase targeting newly synthesized
        TA proteins, and show that CAML mediates membrane insertion of TA proteins.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane is the precise, well-supported localization for this multi-pass
      ER membrane protein.
    action: ACCEPT
    reason: Direct experimental evidence places CAML in the ER membrane as part of
      the GET insertase; the specific localization is correct.
    supported_by:
    - reference_id: file:human/CAMLG/CAMLG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15451437
  qualifier: enables
  review:
    summary: Generic protein binding from a yeast two-hybrid apoptosis screen (IEX-1
      interaction) is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not capture a physiologically interpretable CAML
      function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16243292
  qualifier: enables
  review:
    summary: Generic protein binding from a fibrocystin yeast two-hybrid interaction
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not capture a specific CAML molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22046132
  qualifier: enables
  review:
    summary: Generic protein binding from a SARS-coronavirus host-interactome screen
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not identify a specific CAML function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24658140
  qualifier: enables
  review:
    summary: Generic protein binding from a membrane two-hybrid (MaMTH) assay is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not capture a specific CAML function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Generic protein binding from a proteome-scale interactome map is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome protein binding does not capture a specific
      CAML function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Generic protein binding from an interactome architecture map is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding adds no specific functional information.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: Generic protein binding from an EGFR-network rewiring interactome is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding does not capture a specific CAML function; any EGFR-related
      role is contextual.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic protein binding from a binary interactome reference map is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding adds no specific functional information.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein binding from a dual proteome-scale interactome network
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not capture a specific CAML function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Generic protein binding from a multimodal cell-map interactome is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput protein binding does not capture a specific CAML function.
- term:
    id: GO:0001782
    label: B cell homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: CAML is reported to be essential for survival of peripheral follicular
      B cells (mouse), a contextual cell-type-specific role rather than its core molecular
      function.
    action: KEEP_AS_NON_CORE
    reason: Supported by orthologous/by-similarity evidence and the TACI interaction,
      but secondary to the core GET insertase function; retain as non-core.
    supported_by:
    - reference_id: file:human/CAMLG/CAMLG-uniprot.txt
      supporting_text: peripheral follicular B cells
      reference_section_type: OTHER
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:23041287
  qualifier: located_in
  review:
    summary: Experimental evidence supports ER membrane localization of CAML as part
      of the TA insertion machinery.
    action: ACCEPT
    reason: Consistent with the core ER membrane GET insertase role.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: posttranslationally inserted into the endoplasmic reticulum
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32910895
  qualifier: located_in
  review:
    summary: ER membrane localization is consistent with the structural characterization
      of the WRB/CAML/TRC40 insertase.
    action: ACCEPT
    reason: The correct specific localization, consistent with all experimental and
      structural data.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: targets and inserts tail-anchored (TA)
      reference_section_type: ABSTRACT
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IPI
  original_reference_id: PMID:32910895
  qualifier: part_of
  review:
    summary: Structural study directly establishes CAML as a subunit of the WRB/CAML/TRC40
      GET insertase complex.
    action: ACCEPT
    reason: Cryo-EM and native MS of the human WRB/CAML/TRC40 complex directly support
      GET complex membership.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3
        complexes
      reference_section_type: ABSTRACT
- term:
    id: GO:0045048
    label: protein insertion into ER membrane
  evidence_type: NAS
  original_reference_id: PMID:23041287
  qualifier: involved_in
  review:
    summary: CAML mediates insertion of tail-anchored proteins into the ER membrane;
      this general term is correct and the more specific tail-anchored term is also
      annotated.
    action: ACCEPT
    reason: Directly supported; this is a parent of the more specific tail-anchored
      insertion term and accurately describes CAML's role.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: CAML and WRB synergistically insert TA proteins into the
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31417168
  qualifier: enables
  review:
    summary: The meaningful interaction here is CAML-WRB; bare protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific WRB interaction is captured by the GET complex annotation;
      generic protein binding adds nothing.
    supported_by:
    - reference_id: PMID:31417168
      supporting_text: WRB and CAML depend 
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32187542
  qualifier: enables
  review:
    summary: The meaningful interaction is CAML-WRB within the insertase; bare protein
      binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific WRB/CAML interaction is captured by the GET complex annotation;
      generic protein binding adds nothing.
    supported_by:
    - reference_id: PMID:32187542
      supporting_text: an essential insertase
      reference_section_type: ABSTRACT
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:31417168
  qualifier: located_in
  review:
    summary: Direct evidence places CAML in the ER membrane with a defined three-TM
      C-terminal topology.
    action: ACCEPT
    reason: This study experimentally established CAML ER membrane integration and
      topology; the localization is core and accurate.
    supported_by:
    - reference_id: PMID:31417168
      supporting_text: transmembrane segments (TMs) in its C-terminal region
      reference_section_type: ABSTRACT
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IDA
  original_reference_id: PMID:32187542
  qualifier: involved_in
  review:
    summary: CAML and WRB reciprocally stabilize each other's correct folding/topology
      within the insertase, supporting a protein stabilization role.
    action: KEEP_AS_NON_CORE
    reason: Reciprocal stabilization of WRB is well supported but is an aspect of complex
      assembly downstream of the core insertase function; retain as non-core.
    supported_by:
    - reference_id: PMID:32187542
      supporting_text: When present, WRB can correct the topology of CAML both in vitro
        and in cells.
      reference_section_type: ABSTRACT
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IDA
  original_reference_id: PMID:32910895
  qualifier: part_of
  review:
    summary: Direct structural evidence establishes CAML as a GET complex subunit.
    action: ACCEPT
    reason: Cryo-EM of the human WRB/CAML/TRC40 complex directly supports GET complex
      membership.
    supported_by:
    - reference_id: PMID:32910895
      supporting_text: mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3
        complexes
      reference_section_type: ABSTRACT
- term:
    id: GO:0001782
    label: B cell homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Orthology-based B cell homeostasis annotation reflects the mouse follicular
      B cell survival phenotype; contextual rather than core.
    action: KEEP_AS_NON_CORE
    reason: Supported by orthology and the TACI interaction but secondary to the GET
      insertase molecular function.
    supported_by:
    - reference_id: file:human/CAMLG/CAMLG-uniprot.txt
      supporting_text: peripheral follicular B cells
      reference_section_type: OTHER
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IDA
  original_reference_id: PMID:27226539
  qualifier: involved_in
  review:
    summary: Reconstitution shows CAML (with WRB) is required and sufficient to confer
      tail-anchored protein insertion competence to liposomes.
    action: ACCEPT
    reason: Strong direct biochemical evidence for the core insertion process.
    supported_by:
    - reference_id: PMID:27226539
      supporting_text: in vitro synthesized CAML and WRB together were sufficient to
        confer insertion competence to liposomes
      reference_section_type: ABSTRACT
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23041287
  qualifier: located_in
  review:
    summary: ER localization is well supported and is the core compartment for CAML
      function.
    action: ACCEPT
    reason: Consistent with the more specific ER membrane localization and the insertase
      role.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: posttranslationally inserted into the endoplasmic reticulum
      reference_section_type: ABSTRACT
- term:
    id: GO:0043529
    label: GET complex
  evidence_type: IPI
  original_reference_id: PMID:23041287
  qualifier: part_of
  review:
    summary: CAML is identified as the mammal-specific subunit of the TRC40/GET receptor
      complex with WRB.
    action: ACCEPT
    reason: Directly demonstrated GET complex membership.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: and WRB as components of the TRC40 receptor complex
      reference_section_type: ABSTRACT
- term:
    id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  evidence_type: IMP
  original_reference_id: PMID:23041287
  qualifier: involved_in
  review:
    summary: Mutagenesis/perturbation data support CAML's requirement for tail-anchored
      protein insertion into the ER membrane.
    action: ACCEPT
    reason: Loss-of-function/mutagenesis evidence directly supports the core insertion
      process.
    supported_by:
    - reference_id: PMID:23041287
      supporting_text: binding of TRC40 to CAML is
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20553626
  qualifier: located_in
  review:
    summary: CAML is an integral ER membrane protein with a large cytoplasmic domain;
      a bare cytoplasm localization is misleading relative to the established ER membrane
      residence.
    action: MARK_AS_OVER_ANNOTATED
    reason: Although CAML has cytosol-facing regions, it is an ER membrane protein;
      the ER membrane terms are the accurate localization and bare cytoplasm over-states
      a soluble distribution.
    supported_by:
    - reference_id: file:human/CAMLG/CAMLG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0031397
    label: negative regulation of protein ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:20553626
  qualifier: involved_in
  review:
    summary: This derives from a single study where CAML stabilizes the E3 ligase RNF122;
      it is a narrow, context-specific finding rather than a core CAML function.
    action: KEEP_AS_NON_CORE
    reason: Supported by the RNF122 co-IP study but represents a specific accessory
      interaction, not the conserved GET insertase function.
    supported_by:
    - reference_id: PMID:20553626
      supporting_text: it stabilizes RNF122
      reference_section_type: ABSTRACT
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:20553626
  qualifier: enables
  review:
    summary: CAML binds the RING E3 ligase RNF122; a specific but context-limited single-study
      interaction.
    action: KEEP_AS_NON_CORE
    reason: This specific binding (to RNF122) is supported and more informative than
      bare protein binding, but it is not the core GET function.
    supported_by:
    - reference_id: PMID:20553626
      supporting_text: identified calcium-modulating cyclophilin ligand (CAML) as an
      reference_section_type: ABSTRACT
- term:
    id: GO:0032435
    label: negative regulation of proteasomal ubiquitin-dependent protein catabolic
      process
  evidence_type: IMP
  original_reference_id: PMID:20553626
  qualifier: involved_in
  review:
    summary: This derives from the same RNF122 stabilization study; a narrow, context-specific
      finding rather than a core CAML function.
    action: KEEP_AS_NON_CORE
    reason: Supported by the RNF122 study (CAML stabilizes RNF122) but secondary to
      the core insertase function.
    supported_by:
    - reference_id: PMID:20553626
      supporting_text: it stabilizes RNF122
      reference_section_type: ABSTRACT
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:20553626
  qualifier: involved_in
  review:
    summary: CAML stabilizes RNF122 in this single study; a context-specific accessory
      role rather than core function.
    action: KEEP_AS_NON_CORE
    reason: Supported but narrow; the more general/relevant stabilization role is the
      reciprocal WRB/CAML stabilization within the insertase.
    supported_by:
    - reference_id: PMID:20553626
      supporting_text: it stabilizes RNF122
      reference_section_type: ABSTRACT
- 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 subsumed by the specific ER membrane terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare membrane is uninformative given direct, specific ER membrane localization.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:12919676
  qualifier: located_in
  review:
    summary: ER localization is supported; consistent with the core ER residence of
      CAML.
    action: ACCEPT
    reason: Direct localization evidence consistent with the established ER membrane
      residence.
    supported_by:
    - reference_id: file:human/CAMLG/CAMLG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
      reference_section_type: OTHER
- term:
    id: GO:0006952
    label: defense response
  evidence_type: TAS
  original_reference_id: PMID:7522304
  qualifier: involved_in
  review:
    summary: This broad term derives from the original discovery of CAML as a calcium-signaling
      modulator activating NF-AT/IL-2 in T cells; it is contextual and over-broad relative
      to the core insertase function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying evidence is T-cell calcium signaling, not a defined defense-response
      function; this broad BP term overstates the role of canonical CAML.
    supported_by:
    - reference_id: PMID:7522304
      supporting_text: acts downstream of the TCR and upstream of
      reference_section_type: ABSTRACT
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:7522304
  qualifier: involved_in
  review:
    summary: CAML was originally described as a calcium-signal modulator in T cells,
      but generic signal transduction is over-broad and is not the core conserved function.
    action: MARK_AS_OVER_ANNOTATED
    reason: The historical calcium-signaling role is contextual; the broad signal transduction
      term is uninformative relative to the established GET insertase function.
    supported_by:
    - reference_id: PMID:7522304
      supporting_text: causing an influx of calcium
      reference_section_type: ABSTRACT
references:
- 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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:7522304
  title: Calcium signalling in T cells stimulated by a cyclophilin B-binding protein.
  findings:
  - statement: CAML was identified as a cyclophilin-B-binding protein that elevates
      intracellular calcium and activates NF-AT signaling in T cells.
    supporting_text: causing an influx of calcium
    reference_section_type: ABSTRACT
- id: PMID:12919676
  title: CAML is required for efficient EGF receptor recycling.
  findings:
  - statement: CAML-deficient cells have defective recycling of internalized EGFR to
      the plasma membrane.
    supporting_text: recycling of
    reference_section_type: ABSTRACT
- id: PMID:15451437
  title: Immediate early gene X-1 interacts with proteins that modulate apoptosis.
  findings: []
- id: PMID:16243292
  title: Fibrocystin interacts with CAML, a protein involved in Ca2+ signaling.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20553626
  title: 'RNF122: a novel ubiquitin ligase associated with calcium-modulating cyclophilin
    ligand.'
  findings:
  - statement: CAML binds and stabilizes the RING E3 ligase RNF122 (CAML is not an
      RNF122 substrate).
    supporting_text: it stabilizes RNF122
    reference_section_type: ABSTRACT
- id: PMID:22046132
  title: 'The SARS-coronavirus-host interactome: identification of cyclophilins as
    target for pan-coronavirus inhibitors.'
  findings: []
- id: PMID:23041287
  title: Molecular machinery for insertion of tail-anchored membrane proteins into
    the endoplasmic reticulum membrane in mammalian cells.
  findings:
  - statement: CAML is the mammal-specific TRC40 receptor that, with WRB, mediates
      insertion of tail-anchored proteins into the ER membrane.
    supporting_text: We identify calcium-modulating cyclophilin ligand (CAML) as a
      mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA
      proteins, and show that CAML mediates membrane insertion of TA proteins.
    reference_section_type: ABSTRACT
- id: PMID:24658140
  title: The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein
    interactions in human cells.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:27226539
  title: 'Tail-anchored Protein Insertion in Mammals: FUNCTION AND RECIPROCAL INTERACTIONS
    OF THE TWO SUBUNITS OF THE TRC40 RECEPTOR.'
  findings:
  - statement: In vitro reconstitution shows CAML and WRB together are sufficient to
      confer tail-anchored protein insertion competence to liposomes.
    supporting_text: in vitro synthesized CAML and WRB together were sufficient to
      confer insertion competence to liposomes
    reference_section_type: ABSTRACT
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:31417168
  title: The WRB Subunit of the Get3 Receptor is Required for the Correct Integration
    of its Partner CAML into the ER.
  findings:
  - statement: CAML is integrated into the ER membrane with three C-terminal transmembrane
      segments, dependent on WRB for correct topology.
    supporting_text: is inserted into the ER membrane with three transmembrane segments
      (TMs) in its C-terminal region
    reference_section_type: ABSTRACT
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing
    transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32187542
  title: Differential Modes of Orphan Subunit Recognition for the WRB/CAML Complex.
  findings:
  - statement: WRB and CAML reciprocally regulate each other's folding/stability within
      the insertase.
    supporting_text: When present, WRB can correct the topology of CAML both in vitro
      and in cells.
    reference_section_type: ABSTRACT
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32910895
  title: Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET
    Insertase Complex.
  findings:
  - statement: Cryo-EM of human WRB/CAML/TRC40 defines the GET insertase that inserts
      tail-anchored proteins into the ER membrane.
    supporting_text: mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes
    reference_section_type: ABSTRACT
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: file:human/CAMLG/CAMLG-uniprot.txt
  title: CAMLG UniProtKB record (P49069)
  findings: []
- id: file:human/CAMLG/CAMLG-notes.md
  title: Manual CAMLG curation notes
  findings: []
core_functions:
- description: CAML is a core subunit of the GET (guided entry of tail-anchored proteins)
    insertase complex. Together with WRB/GET1 it forms the ER membrane receptor for
    the cytosolic ATPase TRC40/GET3 and mediates post-translational insertion of tail-anchored
    membrane proteins into the ER membrane.
  directly_involved_in:
  - id: GO:0071816
    label: tail-anchored membrane protein insertion into ER membrane
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:0043529
    label: GET complex
  supported_by:
  - reference_id: PMID:23041287
    supporting_text: We identify calcium-modulating cyclophilin ligand (CAML) as a
      mammal-specific receptor for TRC40, an ATPase targeting newly synthesized TA
      proteins, and show that CAML mediates membrane insertion of TA proteins.
    reference_section_type: ABSTRACT
  - reference_id: PMID:27226539
    supporting_text: in vitro synthesized CAML and WRB together were sufficient to
      confer insertion competence to liposomes
    reference_section_type: ABSTRACT
  - reference_id: PMID:32910895
    supporting_text: mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: Is the historical T-cell calcium-signaling/NF-AT activity of CAML a direct
    function, or an indirect consequence of its role in inserting calcium-handling
    tail-anchored membrane proteins?
- question: Are the B cell survival and EGFR recycling phenotypes of CAML loss explained
    by failure to insert specific tail-anchored client proteins?
suggested_experiments:
- hypothesis: CAML is required for biogenesis of a defined repertoire of tail-anchored
    membrane proteins whose loss explains its physiological and disease phenotypes.
  description: Perform proteome-wide profiling of tail-anchored protein levels/localization
    in CAMLG-knockout versus rescued cells, and reconstitute insertion of candidate
    clients in defined proteoliposomes containing WRB/CAML/TRC40.
  experiment_type: tail-anchored protein biogenesis profiling and reconstitution
- hypothesis: The CDG2Z glycosylation defect results from impaired insertion of tail-anchored
    components of the glycosylation/trafficking machinery rather than a direct glycosylation
    role for CAML.
  description: Quantify N- and O-glycosylation and membrane-trafficking marker localization
    in CAMLG-patient-derived or knockout cells, correlating defects with abundance
    of specific tail-anchored SNAREs and trafficking factors.
  experiment_type: glycomics with membrane trafficking analysis

CAMLG

Gene Description

Existing Annotations Review

Core Functions

CAML is a core subunit of the GET (guided entry of tail-anchored proteins) insertase complex. Together with WRB/GET1 it forms the ER membrane receptor for the cytosolic ATPase TRC40/GET3 and mediates post-translational insertion of tail-anchored membrane proteins into the ER membrane.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: CAMLG (Calcium Modulating Cyclophilin Ligand)

1. Overview and Gene Identity Verification

2. Primary Molecular Function

2.1 Role as a Membrane Insertase

2.2 Molecular Mechanism

2.3 Substrate Specificity

3. Subcellular Localization

4. Structural Architecture

4.1 Domain Organization

4.2 Functional Elements

4.3 Evolutionary Conservation

5. Biochemical Pathway and Biological Processes

5.1 The GET/TRC Pathway

5.2 Key Biological Processes

6. Experimental Evidence

6.1 Structural Studies

6.2 Disease Model Studies

6.3 Mouse Model Studies

6.4 Proteomic Studies

6.5 Biochemical and Cell Biological Studies

7. Recent Developments (2023-2025)

7.1 Rules of Engagement for ER Membrane Protein Biogenesis

7.2 Neuromuscular Disease Implications

7.3 Membrane Insertase Mechanisms

8. Clinical Relevance

9. Summary

Key References

📚 Additional Documentation

Notes

CAMLG (P49069) curation notes

Identity

Core function: GET/TRC insertase receptor for tail-anchored (TA) proteins

GET complex membership and reciprocal stability with WRB

Secondary / historical functions

Calcium signaling (original discovery)

B cell homeostasis

EGFR recycling

RNF122 / ubiquitin-related annotations (PMID:20553626)

Over-annotations / non-informative

Localization

Summary of action plan

Falcon deep research synthesis (2026-06-21)

Pn Notes

CAMLG PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Folding enzyme | Peptidyl-prolyl isomerases | Cyclophilin type

PN row 2: ER proteostasis | Protein transport | GET pathway component

Projected GO annotations (4)

Note

📄 View Raw YAML