Affinage

CAMLG

Guided entry of tail-anchored proteins factor CAMLG · UniProt P49069

Length
296 aa
Mass
33.0 kDa
Annotated
2026-06-09
27 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CAMLG (CAML) is an ER transmembrane protein that, together with WRB, forms the membrane receptor for TRC40/ASNA1 (GET3) and mediates post-translational insertion of tail-anchored proteins into the ER, with CAML's transmembrane segments being essential for a functional receptor that is both necessary and sufficient to support TA targeting and to complement yeast lacking GET1/GET2 (PMID:24392163). CAML's own three-transmembrane topology depends catalytically on WRB; without sufficient WRB, CAML mis-integrates into aberrant topoforms that cluster in the ER and are degraded by the proteasome (PMID:31417168). Through this TRC pathway, CAML governs assembly of Golgi SNAREs—loss of CAML mislocalizes syntaxin-5 and depletes the v-SNARE Bet1L—and is required for correct protein glycosylation and intracellular trafficking, including procathepsin D handling and CD222 retention in the trans-Golgi network (PMID:35262690, PMID:39823474). Biallelic loss-of-function of CAMLG causes a congenital disorder of glycosylation with combined O-linked and type II N-linked defects (PMID:35262690), and neuron-specific CAML deletion produces motor neuron loss and paralysis phenocopied by neuronal ASNA1 deletion, confirming the shared TRC mechanism (PMID:39823474). Beyond TA insertion, CAML acts as a signaling and survival scaffold: it associates ligand-dependently with EGFR and the prolactin receptor to promote their recycling and downstream signaling (PMID:12919676, PMID:21128111), binds p56Lck to negatively regulate TCR signaling and control thymocyte selection (PMID:16111633), and is required for thymocyte and follicular B-cell survival by acting upstream of Bim-dependent apoptosis (PMID:20300112, PMID:22351938). CAML also regulates mitotic spindle function and anaphase chromosome segregation (PMID:19229138), and a separable C-terminal region supports survival and mitotic progression of Myc-driven lymphoma cells independently of TA protein insertion (PMID:28580168).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 Medium

    Established CAML as a signaling intermediate by placing it in the TACI pathway, the first functional assignment for the protein.

    Evidence Dominant-negative mutant and transcriptional reporter assays in Jurkat T cells

    PMID:9311921

    Open questions at the time
    • Molecular mechanism of how CAML links TACI to NF-AT not resolved
    • Direct biochemical contact with TACI not demonstrated
  2. 2003 High

    Showed CAML controls receptor trafficking rather than internalization, defining a recycling role through direct, ligand-dependent association with the EGFR kinase domain.

    Evidence CAML gene knockout MEFs with EGFR trafficking assays and co-immunoprecipitation

    PMID:12919676

    Open questions at the time
    • Structural basis of CAML-EGFR binding unknown
    • How CAML mechanistically routes receptors to recycling not defined
  3. 2005 High

    Extended CAML's signaling-scaffold role to angiotensin II via an ATRAP interaction at the ER and to TCR signaling via p56Lck, and tied it to thymocyte selection.

    Evidence Yeast two-hybrid, co-IP, BRET, reporter assays in HEK293; conditional thymocyte knockout with kinase and flow-cytometry readouts; yeast two-hybrid/co-IP for fibrocystin

    PMID:15668245 PMID:16111633 PMID:16243292

    Open questions at the time
    • The fibrocystin/ciliary interaction (idx 4) is a single co-IP without functional follow-up
    • How a single ER protein integrates multiple receptor signals mechanistically unresolved
  4. 2009 High

    Revealed an unexpected mitotic function, showing CAML loss causes anaphase failure, spindle dysfunction and aneuploidy with a weakened spindle assembly checkpoint.

    Evidence Cre-loxP conditional knockout MEFs with live-cell imaging, SAC assays, and cytogenetics

    PMID:19229138

    Open questions at the time
    • Molecular target of CAML at the spindle/SAC not identified
    • Connection between ER role and mitotic role unclear
  5. 2010 High

    Placed CAML upstream of Bim-dependent apoptosis as a survival factor in thymocytes and ruled out a role in tetherin-mediated HIV restriction, while adding prolactin receptor signaling/recycling to its trafficking repertoire.

    Evidence CAML×Bim double-knockout epistasis with ROS/apoptosis assays; stable shRNA knockdown with HIV release assays; co-IP and siRNA with PRLR signaling and recycling readouts; yeast two-hybrid/co-IP for TMUB1

    PMID:20126395 PMID:20300112 PMID:20582322 PMID:21128111

    Open questions at the time
    • How CAML restrains Bim/ROS mechanistically not defined
    • TMUB1 interaction (idx 7) functionally uncharacterized at this stage
  6. 2012 High

    Demonstrated an ongoing, cell-autonomous anti-apoptotic requirement for CAML in mature follicular B cells, generalizing its survival function beyond development.

    Evidence B cell-specific and inducible conditional knockout with flow cytometry and apoptosis assays

    PMID:22351938

    Open questions at the time
    • Survival pathway in B cells not molecularly mapped
    • Whether the same Bim axis operates in B cells untested here
  7. 2014 High

    Defined CAML's core molecular identity, showing WRB/CAML together are necessary and sufficient as the TRC40 receptor for tail-anchored protein insertion at the ER.

    Evidence Yeast GET1/GET2 complementation, in vivo TA targeting, TRC40 binding affinity measurement, and CAML transmembrane mutagenesis

    PMID:24392163

    Open questions at the time
    • Structure of the WRB/CAML/TRC40 complex not determined
    • Coupling between TA insertion and CAML's signaling roles unresolved
  8. 2017 High

    Separated CAML's survival/mitotic activity from its insertase function, showing a C-terminal WRB-binding region rescues lymphoma cell survival without restoring TA insertion.

    Evidence Inducible knockout in Eμ-Myc lymphoma with domain-deletion rescue, cell cycle analysis, Bcl-2/Bcl-xL rescue, and in vivo tumor regression

    PMID:28580168

    Open questions at the time
    • The effector engaged by the C-terminal domain to promote survival not identified
    • How the same domain drives G2/M progression mechanistically unclear
  9. 2018 Medium

    Linked CAML to calcium signaling, showing TMUB1 displaces CAML from cyclophilin B to lower intracellular Ca2+, and identified a viral subversion of CAML-dependent ER calcium permeability.

    Evidence Co-IP with domain deletions and Ca2+/proliferation readouts in hepatocytes; yeast two-hybrid, colocalization, and Ca2+ permeability assays with viral p7 mutants

    PMID:29967478 PMID:30154321

    Open questions at the time
    • Direct CAML-cyclophilin B-calcineurin biochemistry not fully reconstituted
    • Physiological breadth of CAML calcium control across cell types untested
  10. 2019 High

    Clarified the biogenesis hierarchy, showing WRB catalytically assists CAML's own three-TM topogenesis and that mis-topologized CAML is proteasomally degraded.

    Evidence CAML topology mapping with WRB depletion, proteasome inhibition, immunofluorescence of aberrant clusters, and fractionation

    PMID:31417168

    Open questions at the time
    • Catalytic mechanism by which WRB drives CAML integration not detailed
    • Quality-control machinery degrading mis-topologized CAML not identified
  11. 2022 High

    Connected CAML to human disease, establishing that biallelic CAMLG loss disrupts Golgi SNARE assembly (syntaxin-5, Bet1L) and causes a congenital disorder of glycosylation.

    Evidence Patient fibroblasts with a homozygous splice variant plus siRNA HeLa models, SNARE Western/immunofluorescence, and glycosylation analysis

    PMID:35262690

    Open questions at the time
    • Full spectrum of TA substrates whose mislocalization drives the CDG phenotype not enumerated
    • Genotype-phenotype relationship across additional patients not established
  12. 2025 High

    Demonstrated an in vivo TRC-pathway requirement for CAML in motor neuron survival, with ASNA1 deletion phenocopying CAML loss to confirm the mechanism and tie it to trafficking and glycosylation defects.

    Evidence Multiple neuron-specific Cre lines and hypomorphic mice, spinal cord histology, procathepsin D/CD222/syntaxin-5 trafficking assays, glycosylation analysis, and ASNA1 neuronal-KO epistasis

    PMID:39823474

    Open questions at the time
    • Identity of the critical neuronal TA substrate(s) underlying motor neuron loss not pinpointed
    • Why neurons are particularly vulnerable to TRC-pathway loss not explained

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CAML's single core insertase activity mechanistically gives rise to its diverse receptor-recycling, calcium-signaling, anti-apoptotic, and mitotic functions, and whether these reflect distinct TA substrates or insertion-independent activities.
  • No unifying substrate map linking TA insertion to the signaling/survival phenotypes
  • No high-resolution structure of the WRB/CAML/TRC40 receptor
  • Effector mediating the insertion-independent C-terminal survival function unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9609507 Protein localization 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2
Partners
ASNA1ATRAPEGFRLCKPPIBPRLRTMUB1WRB
Complex memberships
WRB/CAML TRC40 receptor

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CAML acts as a signaling intermediate downstream of TACI (a TNF receptor superfamily member). Cross-linking of TACI activated NF-AT, AP-1, and NF-κB transcription factors, and a dominant-negative CAML mutant specifically blocked TACI-induced NF-AT activation, placing CAML in the TACI signaling pathway. Dominant-negative mutant transfection, transcriptional reporter assays, antibody cross-linking in Jurkat T cells Science Medium 9311921
2003 CAML is required for recycling of internalized EGF receptor (EGFR) back to the plasma membrane. CAML-deficient cells show normal EGFR internalization and EGF-induced signaling but defective receptor recycling and reduced surface EGFR accumulation. CAML directly associates with the kinase domain of EGFR in a ligand-dependent manner. CAML gene knockout (mouse embryonic fibroblasts), EGF receptor trafficking assays (surface accumulation, internalization, recycling), co-immunoprecipitation Developmental Cell High 12919676
2005 CAML interacts with ATRAP (AT1 receptor-associated protein) via its N-terminal hydrophilic domain (aa 1–189) and functions as a signal transducer for angiotensin II-mediated NFAT activation. ATRAP overexpression decreased CAML/Ang II-induced NFAT activation, while ATRAP knockdown increased NFAT activity; the CAML N-terminal domain (aa 1–189) sensitized NFAT activation in response to Ang II. The CAML–ATRAP interaction localizes to ER vesicular structures. Yeast two-hybrid, co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), immunofluorescence colocalization, RNA interference, transcriptional reporter assays in HEK293 cells Journal of Biological Chemistry High 15668245
2005 CAML interacts with p56Lck and regulates its subcellular localization in resting and TCR-stimulated thymocytes. CAML-deficient thymocytes show enhanced p56Lck and ZAP-70 phosphorylation and increased IL-2 production and cell death after TCR stimulation, indicating CAML acts as a negative regulator of p56Lck signaling. CAML is essential for positive selection and suppression of negative selection during thymopoiesis. Conditional CAML knockout in mouse thymocytes, co-immunoprecipitation, kinase phosphorylation assays, IL-2 production assays, flow cytometry of thymocyte populations Immunity High 16111633
2005 The intracellular C-terminus of fibrocystin (ARPKD protein) directly interacts with CAML. Both proteins co-localize in the apical membrane, primary cilia, and basal body of distal nephron cells. Yeast two-hybrid screen, co-immunoprecipitation from COS7 cells, immunofluorescence colocalization Biochemical and Biophysical Research Communications Low 16243292
2009 CAML loss causes anaphase failure and chromosome missegregation. CAML-deficient MEFs fail to segregate chromosomes in anaphase (a 'cut' phenotype), have spindle dysfunction, lagging/misaligned chromosomes and chromatin bridges, a modestly weakened spindle assembly checkpoint (SAC), and increased aneuploidy. CAML functions as a regulator of mitotic spindle function and a modulator of SAC maintenance. Cre-loxP conditional knockout MEFs, live-cell imaging, spindle assembly checkpoint assays, aneuploidy measurement by cytogenetics Cell Cycle High 19229138
2010 CAML-deficient thymocytes accumulate high levels of reactive oxygen species (ROS) and undergo accelerated apoptosis. Genetic removal of the pro-apoptotic BH3-only protein Bim (but not deletion of p53 or Fas) significantly rescued survival of CAML-deficient thymocytes, placing CAML upstream of Bim-dependent apoptosis in thymocyte survival. Conditional knockout, genetic epistasis (CAML KO × Bim KO double mutant mice), ROS measurement, in vitro apoptosis assays Cell Death and Differentiation High 20300112
2010 CAML interacts with TMUB1 (C7orf21/HOPS). The interaction was identified by yeast two-hybrid screen of a brain library and confirmed by co-immunoprecipitation in HEK cells. Both proteins co-localize in the cytoplasm. Yeast two-hybrid, co-immunoprecipitation in HEK cells, immunofluorescence colocalization PloS One Low 20582322
2010 CAML does not contribute to tetherin-mediated restriction of HIV-1 particle release. Stable depletion of CAML in HeLa cells had no effect on cell-surface tetherin levels and did not relieve tetherin-mediated restriction. Stable shRNA knockdown of CAML, flow cytometry for tetherin surface levels, HIV particle release assays PloS One Medium 20126395
2010 CAML is required for prolactin receptor (PRLR) signaling. CAML associates with PRLR and this interaction is augmented by PRL stimulation. CAML silencing impairs PRLR-dependent Stat5 and Mek1/2 activation, PRL internalization with cyclophilin B, PRLR recycling, and Ca2+ mobilization, thereby reducing PRL-dependent proliferation of breast cancer cells. Co-immunoprecipitation, siRNA silencing, signaling pathway assays (Stat5, Mek1/2 phosphorylation), Ca2+ measurement, receptor recycling assays Breast Cancer Research and Treatment Medium 21128111
2012 CAML is essential for survival of peripheral follicular (Fo) B cells. Conditional deletion of CAML in B cells caused reduced Fo B cell numbers, increased cellular turnover, and increased apoptosis after LPS and IL-4 stimulation, establishing an ongoing anti-apoptotic role for CAML in mature B cells. Conditional B cell-specific CAML knockout (CD19-Cre), flow cytometry, in vitro apoptosis assays, inducible gene deletion in mature B cells Journal of Immunology High 22351938
2014 WRB and CAML together form a functional receptor complex for TRC40 (Get3) at the ER membrane and are both necessary and sufficient for tail-anchored (TA) protein targeting and insertion into the ER. The transmembrane segments of CAML are essential for creating a functional receptor with WRB. Binding parameters of TRC40 to the WRB/CAML receptor were determined. Yeast lacking GET1 and GET2 are functionally complemented by WRB and CAML. Yeast complementation assay (GET1/GET2 deletion complementation), in vivo TA protein targeting assays, binding affinity measurement (TRC40 to WRB/CAML), domain mutagenesis of CAML transmembrane segments PloS One High 24392163
2017 CAML supports survival and mitotic progression in Myc-driven B-cell lymphomas independently of its TA protein insertion function. The C-terminal 111 amino acid region of CAML (encompassing the WRB-binding domain but not the TRC40-interaction domain) was sufficient to rescue survival and growth of CAML-deleted lymphoma cells without restoring TA protein insertion. Cell death was blocked by Bcl-2/Bcl-xL overexpression. Loss of CAML caused G2/M arrest with low phospho-histone H3. Tamoxifen-inducible conditional knockout in Eμ-Myc lymphoma cells, domain deletion/rescue experiments, cell cycle analysis, Bcl-2/Bcl-xL overexpression rescue, in vivo tumor regression assay Cell Death Discovery High 28580168
2018 CAML interacts with TMUB1 via TMUB1's TM1 hydrophobic domain. TMUB1 overexpression abolishes the interaction between CAML and its downstream binding partner cyclophilin B, thereby reducing intracellular Ca2+ ([Ca2+]i) and inhibiting hepatocyte proliferation. CAML–cyclophilin B interaction acts upstream of calcineurin to regulate Ca2+ signaling during proliferation. Co-immunoprecipitation in BRL-3A rat hepatocytes, Ca2+ influx measurement, TMUB1 overexpression and knockout, TM1 domain deletion mutant Scientific Reports Medium 29967478
2018 Classical Swine Fever Virus p7 interacts with CAMLG at the ER membrane, and this interaction is required for p7-mediated calcium permeability at the ER. Mutant p7 forms unable to interact with CAMLG failed to mediate calcium permeability and showed decreased virulence. Yeast two-hybrid, confocal colocalization in eukaryotic cells with p7 mutants, calcium permeability assays in ER Viruses Medium 30154321
2019 WRB is required for the correct topological integration of CAML into the ER membrane. Without sufficient WRB, CAML fails to adopt its correct three-transmembrane-segment topology and instead generates two aberrant topoforms that congregate in ER-associated clusters and are degraded by the proteasome. WRB acts catalytically to assist CAML topogenesis, consistent with WRB being a member of the Oxa1 superfamily. Topology mapping (CAML topology determination), WRB knockdown/depletion, proteasome inhibitor treatment, immunofluorescence of aberrant CAML clusters, cell fractionation Scientific Reports High 31417168
2022 Loss of functional CAML (via homozygous splice variant c.633+4A>G) causes mislocalization of syntaxin-5 and drastic reduction of Bet1L (v-SNARE) in patient fibroblasts and siCAMLG-depleted HeLa cells, indicating CAML (as part of the TRC pathway) is required for proper assembly of Golgi SNARE complexes and correct TA protein insertion. This CAML deficiency causes a congenital disorder of glycosylation (combined O-linked and type II N-linked glycosylation defect). Patient fibroblast analysis (homozygous splice variant), siRNA knockdown in HeLa cells, Western blot and immunofluorescence of syntaxin-5 and Bet1L, glycosylation biochemical analysis Human Molecular Genetics High 35262690
2025 CAML is required for motor neuron survival and neuromuscular function via its role in the TRC pathway for TA protein insertion. Neuron-specific CAML deletion causes hind limb weakness, paralysis, and loss of spinal motor neuron cell bodies. CAML depletion perturbs intracellular trafficking: aberrant procathepsin D release, defective CD222 retention in the trans-Golgi network, reduced and mislocalized syntaxin-5, dysfunctional lysosomes, and abnormal protein glycosylation. Neuronal deletion of ASNA1 (TRC40/GET3) produces an identical phenotype, confirming the mechanistic link to the TRC pathway. Neuron-specific conditional knockout (SLICK-H-Cre and synapsin-Cre), global hypomorphic CAML mice, histology of spinal cord, intracellular trafficking assays (procathepsin D secretion, CD222 localization, syntaxin-5 localization), glycosylation analysis, ASNA1 neuronal KO genetic epistasis PLoS Genetics High 39823474

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science (New York, N.Y.) 294 9311921
2003 CAML is required for efficient EGF receptor recycling. Developmental cell 61 12919676
2014 WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane. PloS one 55 24392163
2005 Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation. The Journal of biological chemistry 48 15668245
2000 Molecular cloning and functional characterization of murine transmembrane activator and CAML interactor (TACI) with chromosomal localization in human and mouse. Mammalian genome : official journal of the International Mammalian Genome Society 44 10920230
2005 Fibrocystin interacts with CAML, a protein involved in Ca2+ signaling. Biochemical and biophysical research communications 35 16243292
2015 TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development. The Journal of allergy and clinical immunology 30 26100089
2005 CAML is a p56Lck-interacting protein that is required for thymocyte development. Immunity 30 16111633
2011 Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B-cell dysfunction in patients with Smith-Magenis syndrome. The Journal of allergy and clinical immunology 23 21514638
2009 CAML loss causes anaphase failure and chromosome missegregation. Cell cycle (Georgetown, Tex.) 19 19229138
2019 The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER. Scientific reports 17 31417168
2010 Transmembrane and ubiquitin-like domain containing 1 (Tmub1) regulates locomotor activity and wakefulness in mice and interacts with CAMLG. PloS one 17 20582322
2018 Classical Swine Fever Virus p7 Protein Interacts with Host Protein CAMLG and Regulates Calcium Permeability at the Endoplasmic Reticulum. Viruses 14 30154321
2020 Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma? Cancers 13 32340409
2022 CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking. Human molecular genetics 12 35262690
2010 CAML promotes prolactin-dependent proliferation of breast cancer cells by facilitating prolactin receptor signaling pathways. Breast cancer research and treatment 11 21128111
2010 CAML regulates Bim-dependent thymocyte death. Cell death and differentiation 10 20300112
2017 CAML mediates survival of Myc-induced lymphoma cells independent of tail-anchored protein insertion. Cell death discovery 9 28580168
2025 CAML: Commutative Algebra Machine Learning─A Case Study on Protein-Ligand Binding Affinity Prediction. Journal of chemical information and modeling 6 40518771
2020 Searching for remote homologs of CAML among eukaryotes. Traffic (Copenhagen, Denmark) 6 32715580
2012 Essential role for CAML in follicular B cell survival and homeostasis. Journal of immunology (Baltimore, Md. : 1950) 6 22351938
2024 Identification of Intestinal Lamina Propria Plasma Cells by Surface Transmembrane Activator and CAML Interactor Expression. Journal of immunology (Baltimore, Md. : 1950) 4 38294253
2018 TMUB1 Inhibits BRL-3A Hepatocyte Proliferation by Interfering with the Binding of CAML to Cyclophilin B through its TM1 Hydrophobic Domain. Scientific reports 4 29967478
2010 CAML does not modulate tetherin-mediated restriction of HIV-1 particle release. PloS one 4 20126395
1996 The gene for calcium-modulating cyclophilin ligand (CAMLG) is located on human chromosome 5q23 and a syntenic region of mouse chromosome 13. Genomics 4 8824814
2024 Membrane Interactions of GET1 and GET2 Facilitate Fiber Cell Initiation through the Guided Entry of the TA Protein Pathway in Cotton. Journal of agricultural and food chemistry 1 39467771
2025 Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice. PLoS genetics 0 39823474

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