Affinage

CD2BP2

CD2 antigen cytoplasmic tail-binding protein 2 · UniProt O95400

Length
341 aa
Mass
37.6 kDa
Annotated
2026-06-09
21 papers in source corpus 9 papers cited in narrative 9 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

CD2BP2 (U5-52K) is a nuclear GYF domain adaptor that functions as a pre-spliceosomal assembly factor regulating alternative splicing (PMID:15840814, PMID:26082520). It is the only protein specific to the 20S U5 snRNP that is excluded from the mature U4/U6.U5 tri-snRNP, integrating into the U5 particle through an N-terminal interaction with U5-102K (hPrp6) and a C-terminal GYF domain interaction with U5-15K (PMID:15840814). Crystallography established that the GYF domain binds U5-15K in a polyproline-independent manner, away from the canonical proline-recognition cleft, structurally explaining how the same domain can simultaneously engage proline-rich ligands such as the core spliceosomal protein SmB/B' and the CD2 receptor (PMID:17467737, PMID:15105431). Through its N-terminus, CD2BP2 recruits the phosphatase PP1 to the spliceosome, and it engages the early splicing factor U2AF65 (UAF-1), placing it at two distinct steps of the splicing cascade (PMID:26082520, PMID:22275078). Beyond splicing, CD2BP2 forms a complex with SERBP1 and AGO2 to stabilize miRISC and maintain miRNA levels (PMID:28180320). Conditional knockout in mice shows it is essential for embryogenesis, podocyte integrity, and T cell homeostasis, where its loss drives aberrant exon skipping—including Mdm4 exon 7—and pro-apoptotic gene expression (PMID:26082520, PMID:39308865).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 High

    Defining the binding specificity of the CD2BP2 GYF domain established how this adaptor selects proline-rich partners and linked it to the core spliceosome.

    Evidence Peptide binding, in vitro pulldown, yeast two-hybrid, and immunofluorescence colocalization identifying SmB/B' as a GYF ligand

    PMID:15105431

    Open questions at the time
    • Functional consequence of the SmB/B'-GYF interaction for splicing not established
    • Did not resolve whether nuclear and CD2 receptor binding are mutually exclusive
  2. 2005 High

    Placing CD2BP2 within the 20S U5 snRNP but not the tri-snRNP positioned it as a candidate tri-snRNP assembly factor and mapped its two snRNP contacts.

    Evidence Protein sequencing, yeast two-hybrid, pulldown, and glycerol gradient sedimentation showing U5-102K and U5-15K interactions

    PMID:15840814

    Open questions at the time
    • Direct demonstration that CD2BP2 drives tri-snRNP assembly absent
    • Mechanism of CD2BP2 exclusion from mature tri-snRNP unknown
  3. 2005 Medium

    Refining the GYF recognition motif and mapping its binding surface generalized CD2BP2's role as a modular proline-rich peptide adaptor.

    Evidence Phage display, SPOT analysis, NMR, and yeast two-hybrid identifying PI31 and NPWBP

    PMID:16000308

    Open questions at the time
    • Biological roles of PI31 and NPWBP interactions not pursued
    • No structural complex with these ligands
  4. 2007 High

    The crystal structure resolved how a single GYF domain accommodates both polyproline-independent (U5-15K) and polyproline-dependent (CD2) partners, explaining CD2BP2 bifunctionality.

    Evidence X-ray crystallography of the GYF domain–U5-15K complex with binding-interface validation

    PMID:17467737

    Open questions at the time
    • Structure of full-length CD2BP2 within the snRNP not determined
    • Dynamics of ligand switching not addressed
  5. 2007 Low

    Testing whether CD2 signaling depends on CD2BP2 indicated nuclear partners outcompete CD2 and that CD2 function is largely independent of CD2BP2.

    Evidence HeLa co-expression immunofluorescence and siRNA knockdown in PBMCs with cytokine readout

    PMID:17906334

    Open questions at the time
    • Largely negative/inconclusive results from single methods per assay
    • No quantitative measure of competition between CD2 and nuclear ligands
  6. 2012 Medium

    Identifying a direct U2AF65/UAF-1 interaction extended CD2BP2's action to an early splicing step, beyond tri-snRNP assembly.

    Evidence Genetic screens and co-immunoprecipitation in C. elegans and human cells

    PMID:22275078

    Open questions at the time
    • Functional consequence of the U2AF65 interaction for specific splicing events not shown
    • Single lab; no reciprocal structural mapping
  7. 2015 High

    Conditional knockouts established CD2BP2 as essential in vivo for embryogenesis and podocyte function and linked it mechanistically to PP1 recruitment and alternative exon usage.

    Evidence Conditional mouse knockouts with RNA-seq exon-usage analysis, PP1 co-immunoprecipitation, and histology/EM

    PMID:26082520

    Open questions at the time
    • How PP1 recruitment modulates specific splicing events not resolved
    • Direct splicing targets responsible for podocyte failure not pinpointed
  8. 2017 Medium

    Discovery of a CD2BP2–SERBP1–AGO2 complex revealed a splicing-independent role in stabilizing miRISC and maintaining miRNA abundance.

    Evidence Co-IP, RNA immunoprecipitation, genetic epistasis in C. elegans, and siRNA knockdown in HeLa with miRNA-level readouts

    PMID:28180320

    Open questions at the time
    • Whether miRISC stabilization is direct or a downstream consequence of splicing changes unresolved
    • Domain of CD2BP2 mediating the miRISC interaction not mapped
  9. 2024 Medium

    T cell-specific ablation tied CD2BP2 loss to defined exon-skipping events (Mdm4 exon 7) and apoptosis, explaining its requirement for T cell homeostasis.

    Evidence Conditional T cell knockout with RNA-seq exon-skipping analysis, crosslinking mass spectrometry, and flow cytometry

    PMID:39308865

    Open questions at the time
    • Causal contribution of Mdm4 mis-splicing to T cell death not isolated from other targets
    • Why naive T cells are more sensitive than memory T cells unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CD2BP2 integrates its multiple roles—tri-snRNP assembly, U2AF/early splicing, PP1 recruitment, and miRISC stabilization—into a unified mechanism governing splice-site selection.
  • No structure of CD2BP2 within an assembling spliceosome
  • Rules governing which alternative exons depend on CD2BP2 not defined
  • Mechanistic connection between splicing and miRISC functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3
Partners
AGO2CD2PP1SERBP1SMB/B'U2AF65U5-102KU5-15K
Complex memberships
20S U5 snRNPmiRISC (CD2BP2-SERBP1-AGO2)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CD2BP2 (U5-52K) is a constituent of the 20S U5 snRNP but is absent from the U4/U6.U5 tri-snRNP, making it the only 20S U5-specific protein not integrated into the tri-snRNP. Its N-terminal two-thirds interact with U5-102K (hPrp6), and its C-terminal GYF domain binds U5-15K in a polyproline-independent manner, suggesting CD2BP2 may function in tri-snRNP assembly. Protein sequencing, immunofluorescence, yeast two-hybrid screening, pulldown assays, glycerol gradient sedimentation RNA (New York, N.Y.) High 15840814
2007 Crystal structure of the CD2BP2 GYF domain in complex with U5-15K reveals that the interaction between U5-52K and U5-15K does not involve the canonical polyproline-binding site of the GYF domain nor the common ligand-binding cleft of the thioredoxin-like U5-15K protein, providing the structural basis for the bifunctionality of U5-52K in both spliceosomal assembly and CD2 receptor binding. X-ray crystallography (crystal structure of GYF domain–U5-15K complex) Journal of molecular biology High 17467737
2004 The CD2BP2 GYF domain binds proline-rich sequences with the consensus motif (R/K/G)XXPPGX(R/K). The core spliceosomal protein SmB/B', which contains multiple PPPPGMR motifs, interacts with the CD2BP2 GYF domain both in vitro and in vivo, and CD2BP2 colocalizes with SmB proteins in the nucleus of Jurkat T cells and HeLa cells. Peptide binding assays, in vitro pulldown, yeast two-hybrid, immunofluorescence colocalization The Journal of biological chemistry High 15105431
2005 Novel interaction partners of the CD2BP2 GYF domain include PI31 and NPWBP; the recognition motif was refined by phage display to PPG(W/F/Y/M/L), and NMR spectroscopy revealed a conserved binding surface on the GYF domain for these peptide interactions. Phage display, SPOT analysis, NMR spectroscopy, yeast two-hybrid The Journal of biological chemistry Medium 16000308
2015 CD2BP2 is essential for embryogenesis in mice; conditional knockout causes growth retardation, vascularization defects, and death at embryonic day 10.5. Ablation in macrophages affects alternative splicing of diverse mRNA transcripts. CD2BP2 recruits the phosphatase PP1 to the spliceosome via its N-terminus. Podocyte-specific depletion causes exon usage changes in VEGF and actin regulator genes, foot process effacement, proteinuria, and lethal kidney failure. Conditional gene targeting in mice (KO), RNA-seq/next-generation sequencing of exon usage, co-immunoprecipitation (PP1 interaction), histology/electron microscopy Journal of molecular cell biology High 26082520
2012 C. elegans TEG-1 (CD2BP2 ortholog) directly binds UAF-1 (U2AF65) splicing factor; human CD2BP2 also directly binds UAF-1/U2AF65, indicating that CD2BP2 functions at two distinct steps in the splicing cascade: early (U2AF interaction) and later (U4/U6.U5 tri-snRNP assembly). Genetic screens, co-immunoprecipitation (C. elegans and human cells), nuclear localization assay Developmental dynamics Medium 22275078
2017 TEG-1 (CD2BP2 ortholog in C. elegans) regulates miRISC stability by physically interacting with VIG-1 and complexing with mature let-7 miRNA; loss of teg-1 reduces abundance of multiple miRNA families and destabilizes miRISC effectors VIG-1 and ALG-1. In human HeLa cells, CD2BP2 (human TEG-1 ortholog), SERBP1/PAI-RBP1 (VIG-1 ortholog), and AGO2 (ALG-1 ortholog) form a complex, and knockdown of CD2BP2 results in reduced miRNA levels. Co-immunoprecipitation, RNA immunoprecipitation, genetic epistasis (C. elegans), siRNA knockdown (HeLa cells), Northern blot/quantitative PCR Nucleic acids research Medium 28180320
2007 CD2BP2's nuclear localization is not altered when CD2 and CD2BP2 are co-expressed in HeLa cells, indicating that nuclear proline-rich sequence partners compete effectively with CD2 for GYF domain binding. CD2BP2 knockdown in primary T cells (PBMCs) did not produce a major difference in cytokine expression, suggesting CD2 signaling is at least partially independent of CD2BP2. Immunofluorescence (HeLa co-expression), siRNA knockdown in PBMCs, cytokine expression assay International immunology Low 17906334
2024 T cell-specific ablation of CD2BP2/U5-52K causes increased T cell lymphopenia, T cell death, and a proliferation/differentiation imbalance. This is accompanied by a substantial increase in exon skipping, including skipping of exon 7 in Mdm4, coinciding with upregulation of pro-apoptotic gene expression. Naïve T cells show enhanced sensitivity compared to memory T cells to loss of CD2BP2/U5-52K. Conditional T cell-specific knockout (Cre-lox), RNA-seq (exon skipping analysis), crosslinking mass spectrometry, flow cytometry Frontiers in immunology Medium 39308865

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 MAP kinase signaling specificity mediated by the LIN-1 Ets/LIN-31 WH transcription factor complex during C. elegans vulval induction. Cell 171 9604932
1995 The Caenorhabditis elegans gene lin-1 encodes an ETS-domain protein and defines a branch of the vulval induction pathway. Genes & development 141 8543158
1998 Gain-of-function mutations in the Caenorhabditis elegans lin-1 ETS gene identify a C-terminal regulatory domain phosphorylated by ERK MAP kinase. Genetics 95 9691039
2005 Sumoylation of LIN-1 promotes transcriptional repression and inhibition of vulval cell fates. Development (Cambridge, England) 55 15689373
2005 The human U5 snRNP 52K protein (CD2BP2) interacts with U5-102K (hPrp6), a U4/U6.U5 tri-snRNP bridging protein, but dissociates upon tri-snRNP formation. RNA (New York, N.Y.) 50 15840814
2014 Molecular characterization and expression of CD2BP2 in Nile tilapia (Oreochromis niloticus) in response to Streptococcus agalactiae stimulus. Gene 35 25020258
2006 Identification of cis-regulatory elements from the C. elegans Hox gene lin-39 required for embryonic expression and for regulation by the transcription factors LIN-1, LIN-31 and LIN-39. Developmental biology 34 16782085
2004 Recognition sequences for the GYF domain reveal a possible spliceosomal function of CD2BP2. The Journal of biological chemistry 34 15105431
2007 Structural basis for the bifunctionality of the U5 snRNP 52K protein (CD2BP2). Journal of molecular biology 31 17467737
2005 lin-1 has both positive and negative functions in specifying multiple cell fates induced by Ras/MAP kinase signaling in C. elegans. Developmental biology 25 16140291
2012 TEG-1 CD2BP2 regulates stem cell proliferation and sex determination in the C. elegans germ line and physically interacts with the UAF-1 U2AF65 splicing factor. Developmental dynamics : an official publication of the American Association of Anatomists 23 22275078
2005 Novel interaction partners of the CD2BP2-GYF domain. The Journal of biological chemistry 23 16000308
2004 Identification of residues of the Caenorhabditis elegans LIN-1 ETS domain that are necessary for DNA binding and regulation of vulval cell fates. Genetics 22 15342509
2015 Conversion of the LIN-1 ETS protein of Caenorhabditis elegans from a SUMOylated transcriptional repressor to a phosphorylated transcriptional activator. Genetics 14 25567989
2025 N4-Acetylcytidine-Mediated CD2BP2-DT Drives YBX1 Phase Separation to Stabilize CDK1 and Promote Breast Cancer Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 39976088
2007 Investigating the functional role of CD2BP2 in T cells. International immunology 12 17906334
2015 The GYF domain protein CD2BP2 is critical for embryogenesis and podocyte function. Journal of molecular cell biology 10 26082520
2017 TEG-1 CD2BP2 controls miRNA levels by regulating miRISC stability in C. elegans and human cells. Nucleic acids research 8 28180320
2012 A novel hSH3 domain scaffold engineered to bind folded domains in CD2BP2 and HIV capsid protein. Protein engineering, design & selection : PEDS 7 22988133
2012 Thermodynamic impact of embedded water molecules in the unfolding of human CD2BP2-GYF domain. The journal of physical chemistry. B 4 22624583
2024 The nuclear GYF protein CD2BP2/U5-52K is required for T cell homeostasis. Frontiers in immunology 3 39308865

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