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