ID PIDD1_HUMAN Reviewed; 910 AA. AC Q9HB75; Q59FD1; Q59H10; Q59HC7; Q7Z4P8; Q8NC89; Q8NDL2; Q96C25; Q9NRE6; DT 11-JUL-2006, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 27-MAR-2024, entry version 180. DE RecName: Full=p53-induced death domain-containing protein 1 {ECO:0000305}; DE EC=3.4.21.- {ECO:0000269|PubMed:17159900}; DE AltName: Full=Leucine-rich repeat and death domain-containing protein; DE Contains: DE RecName: Full=PIDD-N {ECO:0000303|PubMed:17159900}; DE Contains: DE RecName: Full=PIDD-C {ECO:0000303|PubMed:17159900}; DE Contains: DE RecName: Full=PIDD-CC {ECO:0000303|PubMed:17159900}; GN Name=PIDD1 {ECO:0000303|PubMed:28397838, ECO:0000312|HGNC:HGNC:16491}; GN Synonyms=LRDD {ECO:0000303|PubMed:10825539}, PIDD GN {ECO:0000303|PubMed:10973264}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY, INTERACTION RP WITH FADD AND MADD, AND VARIANT ARG-331. RX PubMed=10825539; DOI=10.1016/s0167-4838(00)00029-7; RA Telliez J.-B., Bean K.M., Lin L.-L.; RT "LRDD, a novel leucine rich repeat and death domain containing protein."; RL Biochim. Biophys. Acta 1478:280-288(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INDUCTION, AND VARIANT RP ARG-331. RX PubMed=10973264; DOI=10.1038/79102; RA Lin Y., Ma W., Benchimol S.; RT "Pidd, a new death-domain-containing protein, is induced by p53 and RT promotes apoptosis."; RL Nat. Genet. 26:122-127(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANT ARG-331. RC TISSUE=Brain; RA Zan Q., Guo J.H., Yu L.; RL Submitted (JAN-2002) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7), AND VARIANT ARG-331. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4; 5 AND 6), AND VARIANT RP ARG-331. RC TISSUE=Brain, and Spleen; RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., RA Ohara O., Nagase T., Kikuno R.F.; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5), AND VARIANT ARG-331. RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ARG-331. RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP PROTEIN SEQUENCE OF 2-37; 69-93; 103-111; 183-316; 343-357; 415-435; RP 454-497; 552-581; 598-605; 613-623; 626-637; 651-740; 743-759; 768-798 AND RP 826-870, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, RP PHOSPHORYLATION AT SER-299 AND SER-305, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RC TISSUE=Embryonic kidney; RA Bienvenut W.V., Waridel P., Quadroni M.; RL Submitted (MAR-2009) to UniProtKB. RN [9] RP FUNCTION, AND IDENTIFICATION IN PIDDOSOME COMPLEX. RX PubMed=15073321; DOI=10.1126/science.1095432; RA Tinel A., Tschopp J.; RT "The PIDDosome, a protein complex implicated in activation of caspase-2 in RT response to genotoxic stress."; RL Science 304:843-846(2004). RN [10] RP FUNCTION, INTERACTION WITH IKBKG AND RIPK1, AND SUBCELLULAR LOCATION. RX PubMed=16360037; DOI=10.1016/j.cell.2005.09.036; RA Janssens S., Tinel A., Lippens S., Tschopp J.; RT "PIDD mediates NF-kappaB activation in response to DNA damage."; RL Cell 123:1079-1092(2005). RN [11] RP IDENTIFICATION IN PIDDOSOME COMPLEX. RX PubMed=16652156; DOI=10.1038/sj.onc.1209569; RA Vakifahmetoglu H., Olsson M., Orrenius S., Zhivotovsky B.; RT "Functional connection between p53 and caspase-2 is essential for apoptosis RT induced by DNA damage."; RL Oncogene 25:5683-5692(2006). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH CRADD, SUBCELLULAR LOCATION, RP INDUCTION, DOMAIN, AUTOPROTEOLYTIC PROCESSING, ACTIVE SITE, CLEAVAGE SITE, RP AND MUTAGENESIS OF HIS-444; PHE-445; SER-446; PHE-582; PHE-587 AND SER-588. RX PubMed=17159900; DOI=10.1038/sj.emboj.7601473; RA Tinel A., Janssens S., Lippens S., Cuenin S., Logette E., Jaccard B., RA Quadroni M., Tschopp J.; RT "Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 RT and pro-survival NF-kappaB pathway."; RL EMBO J. 26:197-208(2007). RN [13] {ECO:0007744|PDB:2OF5} RP X-RAY CRYSTALLOGRAPHY (3.20 ANGSTROMS) OF 778-883 IN COMPLEX WITH CRADD, RP DOMAIN, AND MUTAGENESIS OF LEU-801; TYR-814; ARG-815; ARG-825; ASP-826; RP LEU-828; GLU-830; PHE-837; ARG-862 AND GLN-863. RX PubMed=17289572; DOI=10.1016/j.cell.2007.01.019; RA Park H.H., Logette E., Raunser S., Cuenin S., Walz T., Tschopp J., Wu H.; RT "Death domain assembly mechanism revealed by crystal structure of the RT oligomeric PIDDosome core complex."; RL Cell 128:533-546(2007). RN [14] RP INVOLVEMENT IN MRT75, AND VARIANT MRT75 863-GLN--ALA-910 DEL. RX PubMed=28397838; DOI=10.1038/mp.2017.60; RA Harripaul R., Vasli N., Mikhailov A., Rafiq M.A., Mittal K., RA Windpassinger C., Sheikh T.I., Noor A., Mahmood H., Downey S., Johnson M., RA Vleuten K., Bell L., Ilyas M., Khan F.S., Khan V., Moradi M., Ayaz M., RA Naeem F., Heidari A., Ahmed I., Ghadami S., Agha Z., Zeinali S., Qamar R., RA Mozhdehipanah H., John P., Mir A., Ansar M., French L., Ayub M., RA Vincent J.B.; RT "Mapping autosomal recessive intellectual disability: combined microarray RT and exome sequencing identifies 26 novel candidate genes in 192 RT consanguineous families."; RL Mol. Psychiatry 23:973-984(2018). RN [15] RP VARIANT MRT75 TRP-815. RX PubMed=29302074; DOI=10.1038/s41380-017-0012-2; RA Hu H., Kahrizi K., Musante L., Fattahi Z., Herwig R., Hosseini M., RA Oppitz C., Abedini S.S., Suckow V., Larti F., Beheshtian M., Lipkowitz B., RA Akhtarkhavari T., Mehvari S., Otto S., Mohseni M., Arzhangi S., Jamali P., RA Mojahedi F., Taghdiri M., Papari E., Soltani Banavandi M.J., Akbari S., RA Tonekaboni S.H., Dehghani H., Ebrahimpour M.R., Bader I., Davarnia B., RA Cohen M., Khodaei H., Albrecht B., Azimi S., Zirn B., Bastami M., RA Wieczorek D., Bahrami G., Keleman K., Vahid L.N., Tzschach A., Gaertner J., RA Gillessen-Kaesbach G., Varaghchi J.R., Timmermann B., Pourfatemi F., RA Jankhah A., Chen W., Nikuei P., Kalscheuer V.M., Oladnabi M., Wienker T.F., RA Ropers H.H., Najmabadi H.; RT "Genetics of intellectual disability in consanguineous families."; RL Mol. Psychiatry 24:1027-1039(2019). RN [16] RP VARIANTS MRT75 447-TRP--ALA-910 DEL AND TRP-862. RX PubMed=34163010; DOI=10.1038/s41431-021-00910-0; RA Zaki M.S., Accogli A., Mirzaa G., Rahman F., Mohammed H., RA Porras-Hurtado G.L., Efthymiou S., Maqbool S., Shukla A., Vincent J.B., RA Hussain A., Mir A., Beetz C., Leubauer A., Houlden H., Gleeson J.G., RA Maroofian R.; RT "Pathogenic variants in PIDD1 lead to an autosomal recessive RT neurodevelopmental disorder with pachygyria and psychiatric features."; RL Eur. J. Hum. Genet. 29:1226-1234(2021). RN [17] RP VARIANT MRT75 637-ARG--ALA-910 DEL, CHARACTERIZATION OF VARIANTS MRT75 RP 863-GLN--ALA-910 DEL AND 815-TRP, AND INTERACTION WITH CRADD. RX PubMed=33414379; DOI=10.1038/s41398-020-01158-w; RA Sheikh T.I., Vasli N., Pastore S., Kharizi K., Harripaul R., Fattahi Z., RA Pande S., Naeem F., Hussain A., Mir A., Islam O., Girisha K.M., Irfan M., RA Ayub M., Schwarzer C., Najmabadi H., Shukla A., Sladky V.C., Braun V.Z., RA Garcia-Carpio I., Villunger A., Vincent J.B.; RT "Biallelic mutations in the death domain of PIDD1 impair caspase-2 RT activation and are associated with intellectual disability."; RL Transl. Psychiatry 11:1-1(2021). CC -!- FUNCTION: Component of the DNA damage/stress response pathway that CC functions downstream of p53/TP53 and can either promote cell survival CC or apoptosis (PubMed:10973264, PubMed:15073321, PubMed:16360037, CC PubMed:17159900). Associated with CRADD and the CASP2 caspase, it forms CC the PIDDosome a complex that activates CASP2 and triggers apoptosis CC (PubMed:15073321, PubMed:17159900). Associated with IKBKG and RIPK1, it CC enhances sumoylation and ubiquitination of IKBKG which is important for CC activation of the transcription factor NF-kappa-B (PubMed:16360037, CC PubMed:17159900). {ECO:0000269|PubMed:10973264, CC ECO:0000269|PubMed:15073321, ECO:0000269|PubMed:16360037, CC ECO:0000269|PubMed:17159900}. CC -!- SUBUNIT: Forms a complex named the PIDDosome with CASP2 and CRADD CC (PubMed:15073321, PubMed:16652156, PubMed:17159900, PubMed:17289572, CC PubMed:33414379). Forms a complex with IKBKG and RIPK1 CC (PubMed:16360037). Interacts with FADD and MADD (PubMed:10825539). CC {ECO:0000269|PubMed:10825539, ECO:0000269|PubMed:15073321, CC ECO:0000269|PubMed:16360037, ECO:0000269|PubMed:16652156, CC ECO:0000269|PubMed:17159900, ECO:0000269|PubMed:17289572, CC ECO:0000269|PubMed:33414379}. CC -!- INTERACTION: CC Q9HB75; P78560: CRADD; NbExp=7; IntAct=EBI-520427, EBI-520375; CC Q9HB75; Q99750: MDFI; NbExp=3; IntAct=EBI-520427, EBI-724076; CC Q9HB75-2; Q9BPX1: HSD17B14; NbExp=3; IntAct=EBI-12326369, EBI-742664; CC Q9HB75-2; Q7Z7F0-4: KHDC4; NbExp=3; IntAct=EBI-12326369, EBI-9089060; CC Q9HB75-2; Q7Z3K3: POGZ; NbExp=3; IntAct=EBI-12326369, EBI-1389308; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16360037, CC ECO:0000269|PubMed:17159900}. Nucleus {ECO:0000269|PubMed:16360037, CC ECO:0000269|PubMed:17159900}. Note=Enriched in the nucleus upon DNA CC damage. {ECO:0000269|PubMed:17159900}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=7; CC Name=1; CC IsoId=Q9HB75-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9HB75-2; Sequence=VSP_019671; CC Name=3; CC IsoId=Q9HB75-3; Sequence=VSP_019666, VSP_019667; CC Name=4; CC IsoId=Q9HB75-4; Sequence=VSP_019665; CC Name=5; CC IsoId=Q9HB75-5; Sequence=VSP_019665, VSP_019669, VSP_019672, CC VSP_019673; CC Name=6; CC IsoId=Q9HB75-6; Sequence=VSP_019664, VSP_019669, VSP_019671, CC VSP_019672, VSP_019673; CC Name=7; CC IsoId=Q9HB75-7; Sequence=VSP_019665, VSP_019668, VSP_019670; CC -!- TISSUE SPECIFICITY: Ubiquitous. {ECO:0000269|PubMed:10825539}. CC -!- INDUCTION: Up-regulated in response to DNA damage. CC {ECO:0000269|PubMed:10973264, ECO:0000269|PubMed:17159900}. CC -!- DOMAIN: The Death domain mediates the interaction with CRADD and the CC formation of a complex composed of 5 PIDD1 and 7 CRADD proteins which CC in turn recruit 7 CASP2 to form the PIDDosome. CC {ECO:0000269|PubMed:17289572}. CC -!- DOMAIN: The LRR repeat-containing domain has a regulatory activity, CC being autoinhibitory for the activation of NF-kappa-B. CC {ECO:0000269|PubMed:17159900}. CC -!- PTM: Undergoes autoproteolytic processing whose extent either directs CC cells towards survival or apoptotic pathways (PubMed:17159900). CC Autoproteolytically cleaved into two main fragments PIDD-N and PIDD-C CC (PubMed:17159900). PIDD-C can be further processed into PIDD-CC, a CC processing which is enhanced by DNA damage (PubMed:17159900). The CC cleavage producing PIDD-C is required for translocation of PIDD1 to the CC nucleus upon DNA damage and activation of NF-kappa-B (PubMed:17159900). CC PIDD-CC mediates the interaction with CRADD and the cleavage producing CC PIDD-CC is required for the activation of CASP2 (PubMed:17159900). CC PIDD-N remains associated with PIDD-C and PIDD-CC after cleavage CC (PubMed:17159900). {ECO:0000269|PubMed:17159900}. CC -!- DISEASE: Intellectual developmental disorder, autosomal recessive 75, CC with neuropsychiatric features and variant lissencephaly (MRT75) CC [MIM:619827]: An autosomal recessive disorder characterized by global CC developmental delay apparent from infancy or early childhood, impaired CC intellectual development, and behavioral and psychiatric abnormalities. CC Some patients present seizures and facial dysmorphism. Brain imaging CC often shows cortical anomalies. {ECO:0000269|PubMed:28397838, CC ECO:0000269|PubMed:29302074, ECO:0000269|PubMed:33414379, CC ECO:0000269|PubMed:34163010}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=BAD92069.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAD92186.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAD92766.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAD38708.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF229178; AAF69491.1; -; mRNA. DR EMBL; AF274972; AAG13461.1; -; mRNA. DR EMBL; AF465246; AAP97716.1; -; mRNA. DR EMBL; AK074893; BAC11272.1; -; mRNA. DR EMBL; AB208832; BAD92069.1; ALT_INIT; mRNA. DR EMBL; AB208949; BAD92186.1; ALT_INIT; mRNA. DR EMBL; AB209529; BAD92766.1; ALT_INIT; mRNA. DR EMBL; AL833849; CAD38708.1; ALT_INIT; mRNA. DR EMBL; BC014904; AAH14904.1; -; mRNA. DR CCDS; CCDS44508.1; -. [Q9HB75-2] DR CCDS; CCDS7716.1; -. [Q9HB75-1] DR RefSeq; NP_665893.2; NM_145886.3. [Q9HB75-1] DR RefSeq; NP_665894.2; NM_145887.3. [Q9HB75-2] DR RefSeq; XP_011518512.1; XM_011520210.2. [Q9HB75-1] DR RefSeq; XP_011518513.1; XM_011520211.2. DR RefSeq; XP_016873482.1; XM_017017993.1. DR PDB; 2OF5; X-ray; 3.20 A; H/I/J/K/L=778-883. DR PDBsum; 2OF5; -. DR AlphaFoldDB; Q9HB75; -. DR SMR; Q9HB75; -. DR BioGRID; 120645; 46. DR ComplexPortal; CPX-3905; Caspase-2 PIDDosome. DR CORUM; Q9HB75; -. DR IntAct; Q9HB75; 17. DR MINT; Q9HB75; -. DR STRING; 9606.ENSP00000337797; -. DR MEROPS; S68.001; -. DR MEROPS; S68.002; -. DR GlyGen; Q9HB75; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9HB75; -. DR PhosphoSitePlus; Q9HB75; -. DR BioMuta; PIDD1; -. DR DMDM; 116242715; -. DR jPOST; Q9HB75; -. DR MassIVE; Q9HB75; -. DR PaxDb; 9606-ENSP00000337797; -. DR PeptideAtlas; Q9HB75; -. DR ProteomicsDB; 81501; -. [Q9HB75-1] DR ProteomicsDB; 81502; -. [Q9HB75-2] DR ProteomicsDB; 81503; -. [Q9HB75-3] DR ProteomicsDB; 81504; -. [Q9HB75-4] DR ProteomicsDB; 81505; -. [Q9HB75-5] DR ProteomicsDB; 81507; -. [Q9HB75-7] DR Antibodypedia; 22664; 198 antibodies from 25 providers. DR DNASU; 55367; -. DR Ensembl; ENST00000347755.10; ENSP00000337797.5; ENSG00000177595.19. [Q9HB75-1] DR Ensembl; ENST00000411829.6; ENSP00000416801.2; ENSG00000177595.19. [Q9HB75-2] DR GeneID; 55367; -. DR KEGG; hsa:55367; -. DR MANE-Select; ENST00000347755.10; ENSP00000337797.5; NM_145886.4; NP_665893.2. DR UCSC; uc001lro.3; human. [Q9HB75-1] DR AGR; HGNC:16491; -. DR CTD; 55367; -. DR DisGeNET; 55367; -. DR GeneCards; PIDD1; -. DR HGNC; HGNC:16491; PIDD1. DR HPA; ENSG00000177595; Low tissue specificity. DR MalaCards; PIDD1; -. DR MIM; 605247; gene. DR MIM; 619827; phenotype. DR neXtProt; NX_Q9HB75; -. DR OpenTargets; ENSG00000177595; -. DR PharmGKB; PA30445; -. DR VEuPathDB; HostDB:ENSG00000177595; -. DR eggNOG; KOG0619; Eukaryota. DR eggNOG; KOG4177; Eukaryota. DR GeneTree; ENSGT00940000161780; -. DR HOGENOM; CLU_017883_0_0_1; -. DR InParanoid; Q9HB75; -. DR OMA; HRDNLGA; -. DR OrthoDB; 894110at2759; -. DR PhylomeDB; Q9HB75; -. DR TreeFam; TF331183; -. DR BioCyc; MetaCyc:ENSG00000177595-MONOMER; -. DR PathwayCommons; Q9HB75; -. DR Reactome; R-HSA-6803207; TP53 Regulates Transcription of Caspase Activators and Caspases. DR SignaLink; Q9HB75; -. DR SIGNOR; Q9HB75; -. DR BioGRID-ORCS; 55367; 13 hits in 1154 CRISPR screens. DR ChiTaRS; PIDD1; human. DR EvolutionaryTrace; Q9HB75; -. DR GeneWiki; LRDD; -. DR GenomeRNAi; 55367; -. DR Pharos; Q9HB75; Tbio. DR PRO; PR:Q9HB75; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q9HB75; Protein. DR Bgee; ENSG00000177595; Expressed in apex of heart and 118 other cell types or tissues. DR ExpressionAtlas; Q9HB75; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:1905369; C:endopeptidase complex; IPI:ComplexPortal. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0005730; C:nucleolus; NAS:ComplexPortal. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005123; F:death receptor binding; TAS:ProtInc. DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB. DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB. DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB. DR GO; GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; IMP:UniProtKB. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:0043065; P:positive regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB. DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR CDD; cd08779; Death_PIDD; 1. DR Gene3D; 2.60.220.30; -; 2. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 2. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR000488; Death_domain. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR019502; Peptidase_S68_pidd. DR InterPro; IPR000906; ZU5_dom. DR PANTHER; PTHR48051; -; 1. DR PANTHER; PTHR48051:SF1; ZGC:77287; 1. DR Pfam; PF00531; Death; 1. DR Pfam; PF13855; LRR_8; 2. DR Pfam; PF10461; Peptidase_S68; 1. DR Pfam; PF00791; ZU5; 2. DR SMART; SM00005; DEATH; 1. DR SMART; SM00364; LRR_BAC; 5. DR SMART; SM00369; LRR_TYP; 7. DR SUPFAM; SSF47986; DEATH domain; 1. DR SUPFAM; SSF52058; L domain-like; 1. DR PROSITE; PS50017; DEATH_DOMAIN; 1. DR PROSITE; PS51450; LRR; 7. DR PROSITE; PS51145; ZU5; 2. DR Genevisible; Q9HB75; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Apoptosis; Cytoplasm; KW Direct protein sequencing; Disease variant; Hydrolase; KW Intellectual disability; Leucine-rich repeat; Nucleus; Phosphoprotein; KW Reference proteome; Repeat. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.8" FT CHAIN 2..910 FT /note="p53-induced death domain-containing protein 1" FT /id="PRO_0000245243" FT CHAIN 2..445 FT /note="PIDD-N" FT /evidence="ECO:0000269|PubMed:17159900" FT /id="PRO_0000445715" FT CHAIN 446..910 FT /note="PIDD-C" FT /evidence="ECO:0000269|PubMed:17159900" FT /id="PRO_0000445716" FT CHAIN 589..910 FT /note="PIDD-CC" FT /evidence="ECO:0000269|PubMed:17159900" FT /id="PRO_0000445717" FT REPEAT 126..147 FT /note="LRR 1" FT REPEAT 149..171 FT /note="LRR 2" FT REPEAT 172..194 FT /note="LRR 3" FT REPEAT 195..216 FT /note="LRR 4" FT REPEAT 218..240 FT /note="LRR 5" FT REPEAT 241..263 FT /note="LRR 6" FT REPEAT 264..285 FT /note="LRR 7" FT DOMAIN 322..454 FT /note="ZU5 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485" FT DOMAIN 455..596 FT /note="ZU5 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485" FT DOMAIN 788..873 FT /note="Death" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00064" FT REGION 1..25 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 423..452 FT /note="Peptidase S68" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485" FT REGION 566..594 FT /note="Peptidase S68" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485" FT REGION 580..716 FT /note="UPA domain" FT /evidence="ECO:0000250" FT REGION 884..910 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 444 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485, FT ECO:0000269|PubMed:17159900" FT ACT_SITE 446 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485, FT ECO:0000269|PubMed:17159900" FT ACT_SITE 586 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485, FT ECO:0000269|PubMed:17159900" FT ACT_SITE 588 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00485, FT ECO:0000269|PubMed:17159900" FT SITE 445..446 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000269|PubMed:17159900" FT SITE 587..588 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000269|PubMed:17159900" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.8" FT MOD_RES 299 FT /note="Phosphoserine" FT /evidence="ECO:0000269|Ref.8" FT MOD_RES 305 FT /note="Phosphoserine" FT /evidence="ECO:0000269|Ref.8" FT VAR_SEQ 1..492 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|Ref.5" FT /id="VSP_019664" FT VAR_SEQ 1..313 FT /note="Missing (in isoform 4, isoform 5 and isoform 7)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:17974005, ECO:0000303|Ref.3, FT ECO:0000303|Ref.5" FT /id="VSP_019665" FT VAR_SEQ 1..146 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10825539" FT /id="VSP_019666" FT VAR_SEQ 579..589 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10825539" FT /id="VSP_019667" FT VAR_SEQ 585..621 FT /note="THFSWYWLWYTTKNCVGGLARKAWERLRLHRVNLIAL -> LALVHHQELCG FT RPGSEGLGAAAAAPCEPHRSAAAPGP (in isoform 7)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_019668" FT VAR_SEQ 589 FT /note="W -> WSVPPSFLSPPPPVCTALLTPSSPR (in isoform 5 and FT isoform 6)" FT /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.5" FT /id="VSP_019669" FT VAR_SEQ 622..910 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_019670" FT VAR_SEQ 704..720 FT /note="Missing (in isoform 2 and isoform 6)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.5" FT /id="VSP_019671" FT VAR_SEQ 759..815 FT /note="RLRGSEGPRRGAGLSLAPLNLGDAETGFLTQSNLLSVAGRLGLDWPAVALHL FT GVSYR -> VGLRDSRGAGQDRGPGVTRVTWWSWGWSPGLNALFPSNRDFEGPRGHGGG FT LASPWHP (in isoform 5 and isoform 6)" FT /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.5" FT /id="VSP_019672" FT VAR_SEQ 816..910 FT /note="Missing (in isoform 5 and isoform 6)" FT /evidence="ECO:0000303|PubMed:17974005, ECO:0000303|Ref.5" FT /id="VSP_019673" FT VARIANT 331 FT /note="Q -> R (in dbSNP:rs10902221)" FT /evidence="ECO:0000269|PubMed:10825539, FT ECO:0000269|PubMed:10973264, ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005, FT ECO:0000269|Ref.3, ECO:0000269|Ref.5" FT /id="VAR_028031" FT VARIANT 447..910 FT /note="Missing (in MRT75)" FT /evidence="ECO:0000269|PubMed:34163010" FT /id="VAR_087344" FT VARIANT 637..910 FT /note="Missing (in MRT75)" FT /evidence="ECO:0000269|PubMed:33414379" FT /id="VAR_087345" FT VARIANT 815 FT /note="R -> W (in MRT75; loss of interaction with CRADD; FT loss of activation of CASP2 protein)" FT /evidence="ECO:0000269|PubMed:29302074, FT ECO:0000269|PubMed:33414379" FT /id="VAR_087346" FT VARIANT 862 FT /note="R -> W (in MRT75)" FT /evidence="ECO:0000269|PubMed:34163010" FT /id="VAR_087347" FT VARIANT 863..910 FT /note="Missing (in MRT75; loss of interaction with CRADD; FT loss of activation of CASP2 protein)" FT /evidence="ECO:0000269|PubMed:28397838, FT ECO:0000269|PubMed:33414379" FT /id="VAR_080765" FT MUTAGEN 444 FT /note="H->Q: Loss of the proteolytic cleavage producing FT PIDD-C." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 445 FT /note="F->H,W: Loss of the proteolytic cleavage producing FT PIDD-C." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 446 FT /note="S->A: Loss of the proteolytic cleavage producing FT PIDD-C. Unable to translocate to the nucleus upon DNA FT damage. No effect on the ability to activate CASP2. FT Complete loss of proteolytic cleavage; when associated with FT A-588." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 446 FT /note="S->C: No effect on the proteolytic cleavage FT producing PIDD-C." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 582 FT /note="F->A: Loss of the proteolytic cleavage producing FT PIDD-CC." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 587 FT /note="F->H: Loss of the proteolytic cleavage producing FT PIDD-CC." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 588 FT /note="S->A: Loss of the proteolytic cleavage producing FT PIDD-CC. Loss of interaction with CRADD and of the ability FT to activate CASP2. No effect on translocation to the FT nucleus upon DNA damage. Complete loss of proteolytic FT cleavage; when associated with A-446." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 588 FT /note="S->C: No effect on the proteolytic cleavage FT producing PIDD-CC." FT /evidence="ECO:0000269|PubMed:17159900" FT MUTAGEN 801 FT /note="L->A: No effect on complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 814 FT /note="Y->A: Loss of complex assembly with CRADD. Loss of FT PIDDosome assembly. Loss of CASP2 activation." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 815 FT /note="R->A: Partial loss of complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 815 FT /note="R->E: Loss of complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 825 FT /note="R->A: Partial loss of complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 825 FT /note="R->E: Partial loss of complex assembly with CRADD. FT Decreased PIDDosome assembly. Decreased CASP2 activation." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 826 FT /note="D->K: Partial loss of complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 828 FT /note="L->E: Loss of complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 830 FT /note="E->K: No effect on complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 837 FT /note="F->D: Loss of complex assembly with CRADD. Loss of FT PIDDosome assembly. Loss of CASP2 activation." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 862 FT /note="R->A: Loss of complex assembly with CRADD. Loss of FT PIDDosome assembly. Loss of CASP2 activation." FT /evidence="ECO:0000269|PubMed:17289572" FT MUTAGEN 863 FT /note="Q->A: Partial loss of complex assembly with CRADD." FT /evidence="ECO:0000269|PubMed:17289572" FT CONFLICT 335 FT /note="V -> A (in Ref. 4; BAC11272)" FT /evidence="ECO:0000305" FT CONFLICT 421 FT /note="W -> L (in Ref. 3; AAP97716)" FT /evidence="ECO:0000305" FT CONFLICT 492 FT /note="S -> F (in Ref. 4; BAC11272)" FT /evidence="ECO:0000305" FT CONFLICT 512 FT /note="A -> V (in Ref. 6; CAD38708)" FT /evidence="ECO:0000305" FT CONFLICT 601 FT /note="G -> E (in Ref. 6; CAD38708)" FT /evidence="ECO:0000305" FT CONFLICT 895 FT /note="A -> V (in Ref. 1; AAF69491)" FT /evidence="ECO:0000305" FT TURN 782..784 FT /evidence="ECO:0007829|PDB:2OF5" FT HELIX 789..797 FT /evidence="ECO:0007829|PDB:2OF5" FT HELIX 803..809 FT /evidence="ECO:0007829|PDB:2OF5" FT HELIX 814..823 FT /evidence="ECO:0007829|PDB:2OF5" FT TURN 824..826 FT /evidence="ECO:0007829|PDB:2OF5" FT HELIX 828..841 FT /evidence="ECO:0007829|PDB:2OF5" FT HELIX 849..859 FT /evidence="ECO:0007829|PDB:2OF5" FT HELIX 863..872 FT /evidence="ECO:0007829|PDB:2OF5" SQ SEQUENCE 910 AA; 99712 MW; 8C98FC64230B57F8 CRC64; MAATVEGPEL EAAAAAGDAS EDSDAGSRAL PFLGGNRLSL DLYPGGCQQL LHLCVQQPLQ LLQVEFLRLS THEDPQLLEA TLAQLPQSLS CLRSLVLKGG QRRDTLGACL RGALTNLPAG LSGLAHLAHL DLSFNSLETL PACVLQMRGL GALLLSHNCL SELPEALGAL PALTFLTVTH NRLQTLPPAL GALSTLQRLD LSQNLLDTLP PEIGGLGSLL ELNLASNRLQ SLPASLAGLR SLRLLVLHSN LLASVPADLA RLPLLTRLDL RDNQLRDLPP ELLDAPFVRL QGNPLGEASP DAPSSPVAAL IPEMPRLFLT SDLDSFPVTP QGCSVTLACG VRLQFPAGAT ATPITIRYRL LLPEPGLVPL GPHDALLSHV LELQPHGVAF QQDVGLWLLF TPPQARRCRE VVVRTRNDNS WGDLETYLEE EAPQRLWAHC QVPHFSWFLV VSRPVSNACL VPPEGTLLCS SGHPGVKVIF PPGATEEPRR VSMQVVRMAG RELQALLGEP EAAVSPLLCL SQSGPPSFLQ PVTVQLPLPS GITGLSLDRS RLHLLYWAPP AATWDDITAQ VVLELTHLYA RFQVTHFSWY WLWYTTKNCV GGLARKAWER LRLHRVNLIA LQRRRDPEQV LLQCLPRNKV DATLRRLLER YRGPEPSDTV EMFEGEEFFA AFERGIDVDA DRPDCVEGRI CFVFYSHLKN VKEVYVTTTL DREAQAVRGQ VSFYRGAVPV RVPEEAEAAR QRKGADALWM ATLPIKLPRL RGSEGPRRGA GLSLAPLNLG DAETGFLTQS NLLSVAGRLG LDWPAVALHL GVSYREVQRI RHEFRDDLDE QIRHMLFSWA ERQAGQPGAV GLLVQALEQS DRQDVAEEVR AVLELGRRKY QDSIRRMGLA PKDPALPGSS APQPPEPAQA //