Affinage

CRADD

Death domain-containing protein CRADD · UniProt P78560

Length
199 aa
Mass
22.7 kDa
Annotated
2026-06-09
31 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRADD (RAIDD) is a bipartite adaptor protein that links death proteases to upstream signaling through two homotypic interaction modules: a C-terminal death domain (DD) that binds the DD of RIP/RIPK1 and PIDD, and an N-terminal CARD that homophilically engages the prodomain of caspase-2 (PMID:8985253, PMID:9044836). Structural work defined both modules — the CARD as a six-helix bundle with opposing basic and acidic patches that constitute the caspase-2 interaction surface (PMID:9695946), and the DD by crystallography as the unit driving PIDDosome assembly (PMID:16434054). CRADD nucleates the PIDDosome through an ordered, conformationally gated mechanism: PIDD-DD must first bind the RAIDD-DD to open the otherwise closed full-length adaptor, permitting subsequent CARD:CARD recruitment of caspase-2 and proximity-induced caspase activation (PMID:24064063, PMID:17329820, PMID:20406701). This adaptor function drives apoptosis in specific contexts, most prominently neuronal death following trophic factor withdrawal, NGF deprivation, or Aβ exposure, where RAIDD is required to assemble with and activate caspase-2 — in neurons independently of PIDD (PMID:15947787, PMID:22515271, PMID:16183742). CRADD/caspase-2 signaling is required for normal cortical development: DD mutations (G128R, F164C, R170C, R170H) abolish caspase-2 activation while leaving PIDD/caspase-2 binding intact and cause thin/thick lissencephaly in patients, with Cradd-knockout mice showing megalencephaly and seizures (PMID:27773430, PMID:30281648). Beyond apoptosis, CRADD restrains inflammatory signaling by binding BCL10 through its CARD to suppress the BCL10–CARMA1 signalosome, limiting cytokine output in T cells and endothelial barrier disruption (PMID:22323537, PMID:24958727), and it scaffolds IKKε–IRF7 interactions through both its CARD and DD to support type I interferon production (PMID:27606466). CRADD is dispensable for Fas-mediated apoptosis and for the tumor-modulatory effects of caspase-2/PIDD1 in Myc-driven lymphoma, indicating its functions are pathway- and context-restricted (PMID:10903735, PMID:25857265).

Mechanistic history

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

    Established CRADD/RAIDD as a bipartite adaptor that physically bridges an upstream kinase to a death protease, answering how caspase-2 is connected to signaling complexes.

    Evidence Yeast two-hybrid, reciprocal co-immunoprecipitation, and domain mapping mapping the DD to RIP and the CARD to caspase-2/CED-3, independently replicated by a second lab the same year

    PMID:8985253 PMID:9044836

    Open questions at the time
    • Did not define the physiological stimulus or higher-order assembly
    • RIP/RIPK1 functional role left uncharacterized
  2. 1998 High

    Defined the structural basis of CARD-mediated caspase-2 recruitment, identifying the charged surface patches that constitute the interaction interface.

    Evidence NMR solution structure of the RAIDD CARD with homology modeling and interface mutagenesis disrupting the caspase-2 interaction

    PMID:9695946

    Open questions at the time
    • Structure of full-length adaptor and how CARD accessibility is regulated not resolved
    • No structure of the CARD:CARD complex itself
  3. 2000 Medium

    Showed CRADD function is pathway-restricted by establishing it is dispensable for Fas-induced apoptosis, and that its CARD drives higher-order oligomeric assemblies under intramolecular control.

    Evidence Cell death assays in RAIDD-deficient lymphoid cells; subcellular fractionation and confocal imaging of domain mutants forming filamentous structures

    PMID:10713730 PMID:10903735

    Open questions at the time
    • Negative Fas result from a single study
    • Functional significance of CARD filaments in endogenous setting unclear
  4. 2004 Medium

    Connected CRADD to neuronal apoptosis, showing CARD-dependent caspase-2 recruitment drives death in neurons.

    Evidence Co-IP, domain mutants, cell death assays and microscopy in PC12 cells and sympathetic neurons showing full-length RAIDD is required for death and aggregate formation

    PMID:14765136

    Open questions at the time
    • Relied on overexpression for the death phenotype
    • Endogenous requirement not yet demonstrated
  5. 2005 High

    Placed RAIDD genetically upstream in PIDD-induced death, establishing it as an obligate adaptor whose loss confers resistance.

    Evidence RAIDD-/- and caspase-2-/- MEFs with caspase activity and death assays showing RAIDD requirement and partial caspase-2 dependence

    PMID:16183742

    Open questions at the time
    • Identity of caspase-2-independent effector downstream of RAIDD unknown
  6. 2006 High

    Demonstrated the endogenous physiological requirement for RAIDD in trophic-deprivation neuronal death and its stimulus specificity, distinguishing caspase-2-dependent from DNA-damage death.

    Evidence siRNA knockdown and dominant-negative CARD fragment expression with pathway-specific death assays; DD crystal structure at 2.0 Å

    PMID:15947787 PMID:16434054

    Open questions at the time
    • Mechanism distinguishing trophic versus DNA-damage death routing not defined
  7. 2010 Medium

    Reconstituted the PIDDosome in vitro and characterized its oligomeric stoichiometry and assembly determinants, defining DD:DD contacts as the assembly driver.

    Evidence Recombinant protein purification, gel filtration, MALS, and dominant-negative point mutants (RAIDD R147E, PIDD Y814A) in biochemical assembly assays

    PMID:17329820 PMID:20406701

    Open questions at the time
    • Did not capture caspase-2-incorporated complex
    • In vitro assembly kinetics may not reflect cellular regulation
  8. 2012 High

    Resolved the in vivo neuronal mechanism, showing RAIDD–caspase-2 complex assembly is required but PIDD is dispensable in neurons, and uncovered a non-apoptotic role suppressing BCL10–CARMA1 inflammatory signaling.

    Evidence RAIDD-/- and PIDD-/- neurons with active caspase-2 detection and co-IP; Cradd-/- T cells/mice with CARD-dependent BCL10 co-IP and cytokine measurement

    PMID:22323537 PMID:22515271

    Open questions at the time
    • PIDD-independent neuronal scaffold for RAIDD not identified
    • How a single CARD partitions between caspase-2 and BCL10 binding unclear
  9. 2013 Medium

    Defined the ordered, conformationally gated assembly mechanism whereby PIDD-DD binding opens closed RAIDD to permit caspase-2 recruitment.

    Evidence Recombinant protein solubility/binding assays reconstituting sequential PIDDosome assembly

    PMID:24064063

    Open questions at the time
    • Structural detail of the closed-to-open transition not visualized
    • In vitro model not validated in cells
  10. 2014 Medium

    Extended CRADD's anti-inflammatory BCL10-suppressing role to endothelial barrier control and established transcriptional regulation of CRADD by HDAC1.

    Evidence Cradd-/- endothelial cells with permeability, cytoskeletal and cytokine readouts plus CP-CRADD rescue; ChIP showing HDAC1 binding the CRADD promoter with siRNA functional rescue

    PMID:24958727 PMID:25360218

    Open questions at the time
    • Single-lab studies
    • Direct competition between CRADD and CARMA1 for BCL10 not structurally defined
  11. 2016 High

    Established CRADD/caspase-2 signaling as required for normal cortical gyration and identified its role in type I interferon production.

    Evidence Co-IP of lissencephaly DD mutants with PIDD/caspase-2, caspase-2 activity assays and Cradd-/- mouse phenotyping; Co-IP and domain-deletion luciferase reporter assays mapping IKKε/IRF7 scaffolding to both CARD and DD

    PMID:27502430 PMID:27606466 PMID:27773430

    Open questions at the time
    • How DD mutations abolish caspase-2 activation despite intact binding not mechanistically resolved
    • IKKε/IRF7 scaffolding mechanism single-lab
  12. 2018 Medium

    Provided the biochemical basis by which lissencephaly DD mutations impair caspase-2 activation while sparing PIDD/caspase-2 binding.

    Evidence Site-directed mutagenesis and recombinant binding assays of TLIS-associated DD mutants

    PMID:30281648

    Open questions at the time
    • Mechanism couples binding-competent assembly to activation failure but lacks a structural model of the activating step

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CRADD partitions a single CARD between pro-apoptotic caspase-2 recruitment and anti-inflammatory BCL10 sequestration, and how DD mutations uncouple PIDDosome binding from caspase-2 activation, remain unresolved.
  • No structure of the activated CARD:caspase-2 or CARD:BCL10 complex
  • Identity of the caspase-2-independent effector downstream of RAIDD unknown
  • Mechanistic coupling of assembly to caspase activation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
BCL10CASP2IKBKEIRF7PIDD1RIPK1
Complex memberships
PIDDosome

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RAIDD/CRADD is a bipartite adaptor molecule: its C-terminal death domain (DD) binds the DD of RIP (a serine/threonine kinase), and its N-terminal CARD (caspase recruitment domain, homologous to ICE/CED-3 prodomains) mediates homophilic binding to caspase-2 (ICH-1) and C. elegans CED-3, directly linking death proteases to signaling pathways. Yeast two-hybrid, co-immunoprecipitation, domain mapping with mutations equivalent to inactivating ced-3 mutations Nature High 8985253
1997 CRADD has an NH2-terminal caspase homology domain that interacts with caspase-2 and a COOH-terminal death domain that interacts with RIP, and CRADD is constitutively expressed in many tissues. Co-immunoprecipitation, domain deletion constructs, overexpression apoptosis assay Cancer research High 9044836
1998 NMR solution structure of the RAIDD CARD reveals six tightly packed helices in a topology homologous to the Fas death domain, with a basic patch and an acidic patch on opposite sides that mediate CARD/CARD interaction with ICH-1/caspase-2; mutagenesis of these patches disrupts the interaction. NMR structure determination, homology modeling, mutagenesis Cell High 9695946
2000 Endogenous RAIDD localizes predominantly to the cytoplasm and, to a lesser extent, the nucleus; co-expression with caspase-2 recruits a fraction of RAIDD to the nucleus and causes CARD-dependent colocalization at discrete subcellular structures. Overexpression of the RAIDD-CARD alone forms filamentous oligomeric structures similar to death effector filaments, partially colocalizing with FADD/FLICE DEFs, suggesting CARD-mediated higher-order complex formation is regulated by intramolecular folding. Subcellular fractionation, immunofluorescence/confocal microscopy, transfection of domain mutants Cell death and differentiation Medium 10713730
2005 PIDD-induced apoptosis and growth suppression in embryonic fibroblasts require the adaptor protein RAIDD; RAIDD-deficient MEFs are resistant to PIDD-induced cell death, which is associated with early activation of caspase-2 and later activation of caspases-3 and -7. Caspase-2 knockout MEFs are only partially resistant, indicating caspase-2 contributes but is not the sole effector downstream of RAIDD. Genetic knockout (RAIDD-/- and caspase-2-/- MEFs), caspase activity assays, cell death assays Proceedings of the National Academy of Sciences of the United States of America High 16183742
2000 RAIDD is dispensable for Fas ligand-induced apoptosis in lymphoid cells; loss of RAIDD does not affect FasL-mediated cell death. Genetic studies in RAIDD-deficient cells, cell death assays Journal of immunology Medium 10903735
2006 Crystal structure of the RAIDD death domain determined at 2.0 Å resolution, revealing structural features important for DD folding, dynamics, and PIDDosome assembly via DD:DD interaction with PIDD. X-ray crystallography at 2.0 Å resolution Journal of molecular biology High 16434054
2004 RAIDD interacts with rat caspase-2 via CARD-CARD interaction in neuronal (PC12) cells; RAIDD overexpression induces caspase-2 CARD- and caspase-9-dependent apoptosis in PC12 cells and sympathetic neurons, correlating with formation of discrete perinuclear aggregates; full-length RAIDD is required for both death and aggregate formation. Co-immunoprecipitation, overexpression with domain mutants, cell death assays, fluorescence microscopy Cell death and differentiation Medium 14765136
2006 Endogenous RAIDD is required for trophic factor withdrawal-induced apoptosis of PC12 cells and sympathetic neurons; siRNA knockdown of RAIDD inhibits trophic deprivation-induced death but not DNA damage-induced (non-caspase-2-mediated) death, indicating RAIDD acts specifically through caspase-2 in this context. siRNA knockdown, dominant-negative CARD fragment expression, cell death assays Cell death and differentiation Medium 15947787
2007 The PIDD DD–RAIDD DD complex forms an oligomeric assembly of ~150 kDa in solution (as measured by gel filtration and MALS), mediated by homotypic DD:DD interactions; the complex was crystallized and diffracted to 3.2 Å. Recombinant protein purification, gel filtration, multi-angle light scattering (MALS), crystallography Acta crystallographica Section F Medium 17329820
2010 PIDDosome assembly is time-dependent and salt concentration-dependent; point mutations R147E in RAIDD and Y814A in PIDD exert dominant-negative effects on PIDDosome formation but cannot disrupt pre-formed PIDDosome complexes. Recombinant protein purification, biochemical assembly assays, site-directed mutagenesis Biochimica et biophysica acta Medium 20406701
2011 In ATLL cells, LBH589 (HDAC inhibitor) activates apoptosis via a RAIDD-initiated pathway; siRNA knockdown experiments showed RAIDD activation is the initiating event upstream of caspase-2 and caspase-9 in this context, and RIPK1 is also required. siRNA knockdown of RAIDD, PIDD, caspase-2, caspase-9, and RIPK1; caspase activity assays; DNA microarray Leukemia Medium 21242994
2012 In neurons, caspase-2 activation and caspase-2-dependent neuronal death induced by NGF deprivation or Aβ treatment require RAIDD but not PIDD; RAIDD and caspase-2 form a complex in neurons treated with these stimuli, demonstrable by co-immunoprecipitation from PIDD-null neurons. Genetic knockout (RAIDD-/- and PIDD-/- neurons), active caspase-2 detection, co-immunoprecipitation, cell death assays The Biochemical journal High 22515271
2012 CRADD interacts with BCL10 through its CARD domain and suppresses the BCL10-CARMA1 interaction; TCR agonist stimulation induces CRADD-BCL10 interaction coincident with reduced BCL10-CARMA1 complex formation; Cradd-deficient T cells and mice produce significantly higher levels of IFN-γ, IL-2, TNF-α, and IL-17 in response to TCR agonists. Co-immunoprecipitation, Cradd-/- primary cells and mice, cytokine measurement Journal of immunology Medium 22323537
2013 PIDD DD mediates and stabilizes the interaction between RAIDD and caspase-2 during PIDDosome assembly: full-length RAIDD in a 'closed' conformation cannot interact with caspase-2 CARD alone; PIDD DD must first bind RAIDD DD to open RAIDD and allow subsequent recruitment of caspase-2 via CARD:CARD interaction. Recombinant protein purification, solubility/binding assays, biochemical reconstitution of the sequential assembly BMB reports Medium 24064063
2014 HDAC1 directly binds the CRADD promoter and downregulates CRADD expression; TSA (HDAC inhibitor) induces CRADD expression to activate caspase-2-dependent apoptosis; HDAC1 siRNA upregulates CRADD in gastric cancer cells. ChIP assay (HDAC1 binding to CRADD promoter), siRNA knockdown, caspase-2 activity assays, Western blot American journal of translational research Medium 25360218
2014 CRADD-deficient murine endothelial cells show heightened BCL10-mediated IL-6 and MCP-1 expression and increased permeability in response to LPS and thrombin, with increased F-actin polymerization and disrupted adherens junctions; delivery of cell-penetrating CP-CRADD protein restores barrier function and suppresses cytokine induction, defining CRADD as an inducible suppressor of BCL10 in endothelial cells. Cradd-/- primary endothelial cells, permeability assays, F-actin staining, recombinant CP-CRADD protein delivery, cytokine measurement The Journal of biological chemistry Medium 24958727
2015 The tumor-modulatory effects of Caspase-2 and Pidd1 in the Eμ-Myc lymphoma model do not require Raidd; Eμ-Myc/Raidd-/- mice show no protection from c-Myc-driven lymphomagenesis, uncoupling Raidd from Caspase-2's tumor suppressor function and Pidd1's tumor-promoting function. Eμ-Myc/Raidd-/- mouse model, tumor onset monitoring, genetic epistasis Cell death and differentiation Medium 25857265
2016 RAIDD interacts with IRF7 and its kinase IKKε by co-immunoprecipitation; RAIDD-deficient cells show dramatically reduced type I IFN activation by IKKε and IRF7; deletion of either the CARD or DD of RAIDD inhibits IKKε/IRF7-mediated IFN-4α activation, indicating both domains are required for this function. Immunoprecipitation, shRNA lentiviral knockdown, IFN-driven dual luciferase reporter assay, domain deletion constructs Cellular physiology and biochemistry Medium 27606466
2016 CRADD death domain mutations (G128R, F164C, R170C, R170H) found in thin lissencephaly patients do not disrupt interactions with caspase-2 or PIDD in co-immunoprecipitation assays, but still abolish CRADD's ability to activate caspase-2, resulting in reduced neuronal apoptosis in vitro; homozygous Cradd knockout mice display megalencephaly and seizures, establishing CRADD/caspase-2 signaling as required for normal cortical gyration. Co-immunoprecipitation of mutant CRADD with PIDD and caspase-2, caspase-2 activity assays, Cradd-/- mouse phenotyping American journal of human genetics High 27773430
2016 TAT-fused peptides containing wild-type helix 3 (H3) from RAIDD block PIDDosome formation in vitro and inhibit rotenone-induced caspase-2-dependent apoptosis in neuronal cells, demonstrating that the H3 region of RAIDD is critical for PIDDosome assembly. In vitro PIDDosome assembly assay, cell-penetrating peptide inhibition, caspase-2 activity assay in neuronal cells Scientific reports Medium 27502430
2018 TLIS-associated RAIDD DD mutations (G128R, F164C, R170C, R170H) were analyzed biochemically; mutagenesis and binding assays revealed the molecular basis by which these mutations impair caspase-2 activation while leaving PIDD/caspase-2 interaction partially intact. Site-directed mutagenesis, recombinant protein expression, biochemical binding assays PloS one Medium 30281648

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 RAIDD is a new 'death' adaptor molecule. Nature 457 8985253
1998 Solution structure of the RAIDD CARD and model for CARD/CARD interaction in caspase-2 and caspase-9 recruitment. Cell 272 9695946
1997 CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP. Cancer research 226 9044836
2005 Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proceedings of the National Academy of Sciences of the United States of America 89 16183742
2000 Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX, and Fas-mediated cell death does not involve DAXX, RIP, or RAIDD. Journal of immunology (Baltimore, Md. : 1950) 56 10903735
2000 Subcellular localization and CARD-dependent oligomerization of the death adaptor RAIDD. Cell death and differentiation 52 10713730
2016 Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. American journal of human genetics 51 27773430
2011 LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway. Leukemia 44 21242994
2012 Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. The Biochemical journal 35 22515271
2006 Crystal structure of RAIDD death domain implicates potential mechanism of PIDDosome assembly. Journal of molecular biology 27 16434054
1998 A 500-kb YAC and BAC contig encompassing the high-growth deletion in mouse chromosome 10 and identification of the murine Raidd/Cradd gene in the candidate region. Genomics 22 9806843
2017 Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly. American journal of medical genetics. Part A 21 28686357
2015 The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd. Cell death and differentiation 20 25857265
2004 RAIDD aggregation facilitates apoptotic death of PC12 cells and sympathetic neurons. Cell death and differentiation 18 14765136
2001 Expression of apoptosis related proteins: RAIDD, ZIP kinase, Bim/BOD, p21, Bax, Bcl-2 and NF-kappaB in brains of patients with Down syndrome. Journal of neural transmission. Supplementum 16 11771742
2013 PIDD mediates and stabilizes the interaction between RAIDD and caspase-2 for the PIDDosome assembly. BMB reports 14 24064063
2009 RAIDD expression is impaired in multidrug resistant osteosarcoma cell lines. Cancer chemotherapy and pharmacology 14 19125251
2007 Crystallization and preliminary X-ray crystallographic studies of the oligomeric death-domain complex between PIDD and RAIDD. Acta crystallographica. Section F, Structural biology and crystallization communications 14 17329820
2019 Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population. European journal of human genetics : EJHG 13 30914828
2010 Identification and analysis of dominant negative mutants of RAIDD and PIDD. Biochimica et biophysica acta 13 20406701
2012 Cutting edge: the "death" adaptor CRADD/RAIDD targets BCL10 and suppresses agonist-induced cytokine expression in T lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 12 22323537
2006 RAIDD is required for apoptosis of PC12 cells and sympathetic neurons induced by trophic factor withdrawal. Cell death and differentiation 12 15947787
2021 CRADD and USP44 mutations in intellectual disability, mild lissencephaly, brain atrophy, developmental delay, strabismus, behavioural problems and skeletal anomalies. European journal of medical genetics 9 33647455
2014 Regulation of CRADD-caspase 2 cascade by histone deacetylase 1 in gastric cancer. American journal of translational research 9 25360218
2016 Rescuing neuronal cell death by RAIDD- and PIDD- derived peptides and its implications for therapeutic intervention in neurodegenerative diseases. Scientific reports 8 27502430
2014 The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli. The Journal of biological chemistry 8 24958727
2009 Purification, crystallization and preliminary x-ray crystallographic studies of RAIDD Death-Domain (DD). International journal of molecular sciences 8 19582216
2003 Overexpression of Raidd cDNA inhibits differentiation of mouse preadipocytes. Cell proliferation 7 12558660
2018 RAIDD mutations underlie the pathogenesis of thin lissencephaly (TLIS). PloS one 5 30281648
2016 RAIDD Mediates TLR3 and IRF7 Driven Type I Interferon Production. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 5 27606466
2024 CRADD and cIAP1 antagonistically regulate caspase-9-mediated apoptosis in teleost. International journal of biological macromolecules 3 39233177

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