CAMLG

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

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.

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