Affinage

C2CD2

C2 domain-containing protein 2 · UniProt Q9Y426

Length
696 aa
Mass
75.5 kDa
Annotated
2026-06-09
11 papers in source corpus 4 papers cited in narrative 3 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C2CD2 is an endoplasmic reticulum protein that organizes ER–plasma membrane (PM) contact sites, functioning as the broadly expressed counterpart to its neuronal paralog TMEM24/C2CD2L (PMID:30819882). At ER-PM junctions C2CD2 assembles into a complex with band 4.1 family proteins, which in turn engage PM proteins including the cell adhesion molecule SynCAM 1, thereby enriching C2CD2-containing junctions specifically at sites of cell-cell contact (PMID:39158698, PMID:38106008). The complex also modulates the Ca2+ responsiveness of these junctions: band 4.1 association renders the junctional pool resistant to Ca2+-triggered shedding from the PM, in contrast to non-cell-adjacent junctions (PMID:39158698, PMID:38106008). C2CD2 itself shows much lower sensitivity to cytosolic Ca2+ elevation than TMEM24, because the C-terminal array of phosphorylation sites that drives Ca2+-dependent dissociation from the PM is only partially conserved (PMID:30819882). Beyond its junctional organization and Ca2+-response properties, the molecular activities and lipid-handling role of C2CD2 have not been further characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2004 Low

    Before any functional work, the gene product's architecture was unknown; sequence analysis defined C2CD2 as a multidomain transmembrane protein paralogous to TMEM24, framing it as a candidate membrane-associated protein.

    Evidence In silico sequence and domain analysis with exon assembly from genomic DNA

    PMID:15289880

    Open questions at the time
    • Predicted topology and the TM24H1/TM24H2 domains were not experimentally validated
    • No subcellular localization or molecular function assigned
    • Paralogy to TMEM24 inferred computationally only
  2. 2019 Medium

    It was unclear whether C2CD2 behaves like the Ca2+-regulated ER-PM tether TMEM24; comparison of the paralogs showed C2CD2 has only partially conserved C-terminal phosphorylation sites and correspondingly weak Ca2+ sensitivity, distinguishing the two proteins mechanistically.

    Evidence Live-cell imaging, subcellular fractionation, phosphorylation-site mapping and Ca2+ manipulation in neurons (focused on TMEM24 with C2CD2 comparison)

    PMID:30819882

    Open questions at the time
    • Direct demonstration of C2CD2 ER-PM tethering and lipid transport not shown in this study
    • Tissue context for C2CD2's reduced Ca2+ response not functionally tested
    • Single lab
  3. 2024 Medium

    How ER-PM junctions become spatially targeted was unknown; identification of a C2CD2/band 4.1 complex linked to SynCAM 1 established that these junctions are enriched at cell-cell contacts and that band 4.1 protects the junctional pool from Ca2+-triggered PM release.

    Evidence Unbiased proximity ligation, Co-IP/complex identification, live-cell imaging and Ca2+ manipulation

    PMID:38106008 PMID:39158698

    Open questions at the time
    • Direct C2CD2-band 4.1 binding interface not defined
    • Functional consequence of contact-site enrichment for the cell unresolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical lipid-transport activity of C2CD2 and the downstream physiological role of its ER-PM contact organization remain undefined.
  • No reconstituted lipid-transfer assay for C2CD2
  • No structural model of the C2CD2/band 4.1 complex
  • Tissue-level or organismal phenotype not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2
Partners
CADM1EPB41TMEM24

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 TMEM24/C2CD2L (the paralog of C2CD2) populates ER-PM contacts in resting neurons but is transiently redistributed throughout the ER upon cytosolic Ca2+ elevation; this dissociation from the plasma membrane is mediated by phosphorylation of an array of C-terminal sites. C2CD2, the paralog primarily expressed in non-neuronal tissues, has only partially conserved phosphorylation sites and correspondingly displays much lower sensitivity to Ca2+ elevations, establishing a mechanistic distinction between the two paralogs. Live-cell imaging, subcellular fractionation, phosphorylation site mapping, experimental Ca2+ manipulation in neurons Proceedings of the National Academy of Sciences of the United States of America Medium 30819882
2024 C2CD2 (and its paralog TMEM24) form a complex with band 4.1 family proteins at ER-PM junctions; band 4.1 in turn binds plasma membrane proteins including the cell adhesion molecule SynCAM 1. This complex enriches C2CD2-containing ER-PM junctions specifically at sites of cell-cell contact, and when band 4.1 is part of the junction, TMEM24 at cell-adjacent ER-PM junctions is not shed from the PM upon Ca2+ rise, unlike TMEM24 at non-cell-adjacent junctions. Unbiased proximity ligation analysis, Co-IP/complex identification, live-cell imaging, Ca2+ manipulation The Journal of cell biology Medium 38106008 39158698
2004 Bioinformatics characterization established that C2CD2 (C21orf25) encodes a 696-aa type II transmembrane protein with an N-terminal short cytoplasmic region, a single transmembrane domain, and a C-terminal extracellular region containing two novel conserved domains (TM24H1 and TM24H2), paralogous to TMEM24 at chromosome 11q23.3. Bioinformatics/in silico sequence and domain analysis; exon assembly from genomic sequence International journal of oncology Low 15289880

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Lipid transporter TMEM24/C2CD2L is a Ca2+-regulated component of ER-plasma membrane contacts in mammalian neurons. Proceedings of the National Academy of Sciences of the United States of America 56 30819882
2015 Recurrent fusion transcripts detected by whole-transcriptome sequencing of 120 primary breast cancer samples. Genes, chromosomes & cancer 37 26227178
2015 Genetics of hand grip strength in mid to late life. Age (Dordrecht, Netherlands) 18 25637336
2017 Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort. Scientific reports 12 29158487
2024 A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts. The Journal of cell biology 7 39158698
2004 Identification and characterization of TMEM24 family genes in silico. International journal of oncology 7 15289880
2024 Prenatal EDC exposure, DNA Methylation, and early childhood growth: A prospective birth cohort study. Environment international 5 38986426
2019 Application of Differentially Methylated Loci in Clinical Diagnosis of Trisomy 21 Syndrome. Genetic testing and molecular biomarkers 4 30986102
2024 Identification of a Potential PGK1 Inhibitor with the Suppression of Breast Cancer Cells Using Virtual Screening and Molecular Docking. Pharmaceuticals (Basel, Switzerland) 2 39770478
2023 A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts. bioRxiv : the preprint server for biology 1 38106008
2026 Integrated multi-omics profiling reveals novel molecular biomarkers and pathways associated with Fragile X-associated tremor/ataxia syndrome. Frontiers in molecular neuroscience 0 42077546

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