GRAM4_HUMAN
ID GRAM4_HUMAN Reviewed; 578 AA.
AC Q6IC98; A9IN51; A9IN57; Q68EN0; Q9UGE6; Q9Y4B9;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=GRAM domain-containing protein 4 {ECO:0000305};
DE AltName: Full=Death-inducing protein;
GN Name=GRAMD4 {ECO:0000312|HGNC:HGNC:29113}; Synonyms=DIP, KIAA0767;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=9872452; DOI=10.1093/dnares/5.5.277;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Miyajima N., Tanaka A.,
RA Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XI. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 5:277-286(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Embryonic carcinoma;
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 [6]
RP INDUCTION.
RX PubMed=11937641; DOI=10.1093/nar/30.8.1859;
RA Stanelle J., Stiewe T., Theseling C.C., Peter M., Puetzer B.M.;
RT "Gene expression changes in response to E2F1 activation.";
RL Nucleic Acids Res. 30:1859-1867(2002).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=15565177; DOI=10.1038/sj.cdd.4401532;
RA Stanelle J., Tu-Rapp H., Puetzer B.M.;
RT "A novel mitochondrial protein DIP mediates E2F1-induced apoptosis
RT independently of p53.";
RL Cell Death Differ. 12:347-357(2005).
RN [8]
RP TISSUE SPECIFICITY.
RX PubMed=18302964; DOI=10.1016/j.lfs.2008.01.009;
RA Sen S., Ateeq B., Sharma H., Datta P., Gupta S.D., Bal S., Kumar A.,
RA Singh N.;
RT "Molecular profiling of genes in squamous cell lung carcinoma in Asian
RT Indians.";
RL Life Sci. 82:772-779(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-24 AND SER-28, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [10]
RP VARIANT ILE-159.
RX PubMed=16225677; DOI=10.1186/1471-244x-5-36;
RA Stoeber G., Kohlmann B., Iekiera M., Rubie C., Gawlik M.,
RA Moeller-Ehrlich K., Meitinger T., Bettecken T.;
RT "Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-
RT linked periodic catatonia.";
RL BMC Psychiatry 5:36-36(2005).
CC -!- FUNCTION: Plays a role as a mediator of E2F1-induced apoptosis in the
CC absence of p53/TP53 (PubMed:15565177). Plays a role as a mediator of
CC E2F1-induced apoptosis in the absence of p53/TP53. Inhibits TLR9
CC response to nucelic acids and regulates TLR9-mediated innate immune
CC response (By similarity). {ECO:0000250|UniProtKB:Q8CB44,
CC ECO:0000269|PubMed:15565177}.
CC -!- SUBUNIT: Interacts with RTN4 (isoform B).
CC {ECO:0000250|UniProtKB:Q8CB44}.
CC -!- INTERACTION:
CC Q6IC98; Q53TS8: C2CD6; NbExp=3; IntAct=EBI-10962409, EBI-739879;
CC Q6IC98; Q8IYE0: CCDC146; NbExp=3; IntAct=EBI-10962409, EBI-10749669;
CC Q6IC98; Q8IYI6: EXOC8; NbExp=3; IntAct=EBI-10962409, EBI-742102;
CC Q6IC98; Q8IZU0: FAM9B; NbExp=3; IntAct=EBI-10962409, EBI-10175124;
CC Q6IC98; O95257: GADD45G; NbExp=3; IntAct=EBI-10962409, EBI-448202;
CC Q6IC98; Q96QG7: MTMR9; NbExp=3; IntAct=EBI-10962409, EBI-744593;
CC Q6IC98; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-10962409, EBI-741158;
CC Q6IC98; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-10962409, EBI-742388;
CC Q6IC98; Q9H788: SH2D4A; NbExp=3; IntAct=EBI-10962409, EBI-747035;
CC Q6IC98; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-10962409, EBI-358489;
CC Q6IC98; B2RWP4: TACC2; NbExp=3; IntAct=EBI-10962409, EBI-14211313;
CC -!- SUBCELLULAR LOCATION: Mitochondrion membrane {ECO:0000305}; Multi-pass
CC membrane protein {ECO:0000305}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q8CB44}; Multi-pass membrane protein
CC {ECO:0000255}. Note=Colocalizes with COX4I1.
CC {ECO:0000269|PubMed:15565177}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6IC98-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6IC98-2; Sequence=VSP_032771;
CC -!- TISSUE SPECIFICITY: Expressed in lung and in primary lung squamous cell
CC carcinoma (LSCC). {ECO:0000269|PubMed:18302964}.
CC -!- INDUCTION: Up-regulated in the mitochondria by E2F1 after addition of
CC 4-hydroxytamoxifen (at protein level). {ECO:0000269|PubMed:11937641,
CC ECO:0000269|PubMed:15565177}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA34487.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB018310; BAA34487.2; ALT_INIT; mRNA.
DR EMBL; CR456470; CAG30356.1; -; mRNA.
DR EMBL; AL096766; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL021392; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471138; EAW73432.1; -; Genomic_DNA.
DR EMBL; BC080189; AAH80189.1; -; mRNA.
DR EMBL; BC129837; AAI29838.1; -; mRNA.
DR CCDS; CCDS33672.1; -. [Q6IC98-1]
DR RefSeq; NP_055939.1; NM_015124.4. [Q6IC98-1]
DR RefSeq; XP_006724233.1; XM_006724170.3. [Q6IC98-1]
DR RefSeq; XP_016884159.1; XM_017028670.1. [Q6IC98-1]
DR AlphaFoldDB; Q6IC98; -.
DR SMR; Q6IC98; -.
DR BioGRID; 116766; 36.
DR IntAct; Q6IC98; 15.
DR STRING; 9606.ENSP00000385689; -.
DR iPTMnet; Q6IC98; -.
DR PhosphoSitePlus; Q6IC98; -.
DR BioMuta; GRAMD4; -.
DR DMDM; 74748754; -.
DR EPD; Q6IC98; -.
DR jPOST; Q6IC98; -.
DR MassIVE; Q6IC98; -.
DR MaxQB; Q6IC98; -.
DR PaxDb; Q6IC98; -.
DR PeptideAtlas; Q6IC98; -.
DR PRIDE; Q6IC98; -.
DR ProteomicsDB; 66380; -. [Q6IC98-1]
DR ProteomicsDB; 66381; -. [Q6IC98-2]
DR Antibodypedia; 28118; 52 antibodies from 13 providers.
DR DNASU; 23151; -.
DR Ensembl; ENST00000361034.7; ENSP00000354313.3; ENSG00000075240.17. [Q6IC98-1]
DR Ensembl; ENST00000406902.6; ENSP00000385689.1; ENSG00000075240.17. [Q6IC98-1]
DR Ensembl; ENST00000408031.1; ENSP00000385851.1; ENSG00000075240.17. [Q6IC98-2]
DR GeneID; 23151; -.
DR KEGG; hsa:23151; -.
DR MANE-Select; ENST00000406902.6; ENSP00000385689.1; NM_015124.5; NP_055939.1.
DR UCSC; uc003bhx.4; human. [Q6IC98-1]
DR CTD; 23151; -.
DR DisGeNET; 23151; -.
DR GeneCards; GRAMD4; -.
DR HGNC; HGNC:29113; GRAMD4.
DR HPA; ENSG00000075240; Tissue enhanced (liver).
DR MIM; 613691; gene.
DR neXtProt; NX_Q6IC98; -.
DR OpenTargets; ENSG00000075240; -.
DR PharmGKB; PA162390212; -.
DR VEuPathDB; HostDB:ENSG00000075240; -.
DR eggNOG; ENOG502QPMR; Eukaryota.
DR GeneTree; ENSGT00390000010968; -.
DR HOGENOM; CLU_028241_0_0_1; -.
DR InParanoid; Q6IC98; -.
DR OMA; XYLCFES; -.
DR OrthoDB; 1148554at2759; -.
DR PhylomeDB; Q6IC98; -.
DR TreeFam; TF320445; -.
DR PathwayCommons; Q6IC98; -.
DR SignaLink; Q6IC98; -.
DR BioGRID-ORCS; 23151; 21 hits in 1083 CRISPR screens.
DR ChiTaRS; GRAMD4; human.
DR GenomeRNAi; 23151; -.
DR Pharos; Q6IC98; Tbio.
DR PRO; PR:Q6IC98; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; Q6IC98; protein.
DR Bgee; ENSG00000075240; Expressed in mucosa of transverse colon and 153 other tissues.
DR ExpressionAtlas; Q6IC98; baseline and differential.
DR Genevisible; Q6IC98; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0034164; P:negative regulation of toll-like receptor 9 signaling pathway; ISS:UniProtKB.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
DR CDD; cd13221; PH-GRAM_GRAMDC4; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR004182; GRAM.
DR InterPro; IPR037847; GRAMDC4.
DR InterPro; IPR037845; GRAMDC4_PH-GRAM.
DR InterPro; IPR011993; PH-like_dom_sf.
DR PANTHER; PTHR37402; PTHR37402; 1.
DR Pfam; PF02893; GRAM; 1.
DR SMART; SM00568; GRAM; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Coiled coil; Endoplasmic reticulum;
KW Membrane; Mitochondrion; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..578
FT /note="GRAM domain-containing protein 4"
FT /id="PRO_0000328742"
FT TRANSMEM 240..260
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 334..354
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 356..376
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 445..523
FT /note="GRAM"
FT REGION 23..58
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 136..159
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 415..435
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 83..143
FT /evidence="ECO:0000255"
FT COMPBIAS 141..159
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 24
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 28
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT VAR_SEQ 1..477
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_032771"
FT VARIANT 159
FT /note="S -> I (in dbSNP:rs36211078)"
FT /evidence="ECO:0000269|PubMed:16225677"
FT /id="VAR_042505"
SQ SEQUENCE 578 AA; 66408 MW; 7CE03B34F979D93D CRC64;
MLRRLDKIRF RGHKRDDFLD LAESPNASDT ECSDEIPLKV PRTSPRDSEE LRDPAGPGTL
IMATGVQDFN RTEFDRLNEI KGHLEIALLE KHFLQEELRK LREETNAEML RQELDRERQR
RMELEQKVQE VLKARTEEQM AQQPPKGQAQ ASNGAERRSQ GLSSRLQKWF YERFGEYVED
FRFQPEENTV ETEEPLSARR LTENMRRLKR GAKPVTNFVK NLSALSDWYS VYTSAIAFTV
YMNAVWHGWA IPLFLFLAIL RLSLNYLIAR GWRIQWSIVP EVSEPVEPPK EDLTVSEKFQ
LVLDVAQKAQ NLFGKMADIL EKIKNLFMWV QPEITQKLYV ALWAAFLASC FFPYRLVGLA
VGLYAGIKFF LIDFIFKRCP RLRAKYDTPY IIWRSLPTDP QLKERSSAAV SRRLQTTSSR
SYVPSAPAGL GKEEDAGRFH STKKGNFHEI FNLTENERPL AVCENGWRCC LINRDRKMPT
DYIRNGVLYV TENYLCFESS KSGSSKRNKV IKLVDITDIQ KYKVLSVLPG SGMGIAVSTP
STQKPLVFGA MVHRDEAFET ILSQYIKITS AAASGGDS
