CRADD/RAIDD bridges death-domain proteins to caspase-2. The original human domain assays distinguish CASP2 recruitment from RIP death-domain binding [PMID:9044836 “DD that interacts with RIP”]. PIDD-CC, rather than PIDD-C, is the RAIDD-associated processed species in the later human-cell experiments. A purified PIDD/RAIDD death-domain core has five PIDD and seven RAIDD chains, but this is not a measured invariant stoichiometry of an intact cellular PIDDosome. The experimentally supported synthesis is a noncatalytic signaling adaptor in a caspase complex and apoptotic signaling, chiefly in cytosol. [PMID:15073321 “adaptor protein RAIDD”]. See the primary-source access guide for genuine originals, construct boundaries and access limits.
The original Nature experiments distinguish direct recruitment from bridged association. RAIDD associates with TRADD only when RIP is present, and engineered TNFR1 association requires both TRADD and RIP. Those positive complexes remain supported generic binding; they do not by themselves demonstrate direct receptor recognition or ligand-triggered extrinsic apoptosis. The separate original CRADD paper proposes receptor involvement. Its adaptor-activity premise therefore overstates the specific extrinsic receptor-process annotation, while broad apoptotic signaling is well supported. Mouse RAIDD-null fibroblasts remain sensitive to TNF in the tested model but resist PIDD overexpression; this does not establish a universal negative for every receptor context [PMID:16183742 “PIDD-induced apoptosis and growth suppression”].
CASP2 binary and co-complex records can be refined by the actual caspase class. The 2000 CASP2L-Pro study is construct-specific: the bound prodomain product lacks the last CARD helix, and the literal interaction record identifies residues18–106. This is not evidence for an active full-length protease in that experiment. PIDD1 interactions have independently demonstrated death-domain specificity. ACTN2 interaction supports muscle alpha-actinin binding, without making CRADD an actin crosslinker or sarcomeric component. Positive KCTD9, BBS5, APPL2 and TRIM54 records remain generic non-core binding where a stronger class is not established. A participant ROGID authenticates its reference sequence, not necessarily an untagged full-length experimental construct.
Tax binding is also retained. The experimentally positive interaction is separate from the disputed claim that Tax itself is an E3 ubiquitin ligase. The P14079 class inference points to the P03409 Tax record; original purified-protein results in PMID:27082114 support E3 activity, while PMID:28103322 tests active bacterial and insect-cell Tax preparations and reports conflicting results with an E3 positive control. That conflict blocks a confident ligase-binding refinement here; it does not invalidate the CRADD–Tax association.
Subcellular and signaling contexts require similar precision. Mouse FLAG-Cradd in mIMCD3 cells supports the nuclear/cytoplasmic donor assignments. Human-cell CASP2 proximity and fractionation experiments identify a cytoplasmic RAIDD-dependent/PIDD-independent platform and a nucleolar platform requiring both proteins [PMID:28432080 “a nucleolar platform that requires both PIDD and RAIDD”]. These experiments do not directly image endogenous CRADD. Nuclear and nucleolar locations are retained as contextual functions rather than made obligatory primary locations. Human U2OS knockdown and 293T expression experiments place RAIDD upstream of CASP2-mediated MDM2 cleavage and p53 reinforcement after damage; CRADD is not the protease [PMID:21726810 “RAIDD knockdown in U2OS cells”].
The CARD8-focused paper PMID:11821383 includes CRADD as an actual MCF-7 apoptotic positive control in Figure7C. The source’s abstract alone would miss this. Its targeted original Methods/Results/caption support retention; CARD8-specific NF-kappaB and caspase-1 findings are not transferred. In contrast, PMID:19593445 was independently recovered and read in full: its targeted BAD/LNCaP/C4-2 and xenograft experiments do not supply the CRADD cellular-mechanical-response annotation. The specific citation is MISCITED. This conclusion is based on the complete experimental scope, not the title, abstract or a universal claim that CRADD cannot respond to mechanical stimuli.
The current human protein has199 residues; the second listed product has103 residues after replacement101–199 with CWP. It retains the CARD region but loses the canonical death domain. No equivalent PIDD-binding or cellular signaling function is assigned to the short product on that sequence observation alone. Clinical and experimental CRADD variants also distinguish association from successful activation: several can retain partner binding while impairing CASP2 activation and neuronal apoptosis [PMID:27773430 “resulting in reduced neuronal apoptosis in vitro”]. The human phenotype and model-system tests support a neural consequence of disrupted signaling, without adding a separate developmental process annotation here.
The current PTHR15034 tree places all four literal IBD nodes on the human path. Human CRADD appearing among the descendant evidence is expected and is not circular. The fly Dronc localization assay used GFP-Dronc in mouse NIH3T3 cells; species and host are retained separately. Full current ARBA conditions were evaluated, with matching branches1480 (cytoplasm) and25 (positive apoptosis). The evidence index retains exact source assertions, selected raw interaction/donor records, typed term relationships, rule conditions and source URLs. This authored provenance is not a second biological experiment.