GSDMA_HUMAN
ID GSDMA_HUMAN Reviewed; 445 AA.
AC Q96QA5; Q32MC5; Q86VE7; Q8N1M6;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 4.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=Gasdermin-A {ECO:0000305};
DE AltName: Full=Gasdermin-1;
DE Contains:
DE RecName: Full=Gasdermin-A, N-terminal {ECO:0000305};
DE Short=GSDMA-NT {ECO:0000305};
DE Contains:
DE RecName: Full=Gasdermin-A, C-terminal {ECO:0000305};
DE Short=GSDMA-CT {ECO:0000305};
GN Name=GSDMA {ECO:0000312|HGNC:HGNC:13311};
GN Synonyms=GSDM {ECO:0000303|PubMed:10967128, ECO:0000303|PubMed:17471240},
GN GSDM1; ORFNames=FKSG9 {ECO:0000303|Ref.2};
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], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND VARIANTS LEU-128 AND LYS-130.
RC TISSUE=Stomach;
RX PubMed=17471240; DOI=10.1038/sj.onc.1210475;
RA Saeki N., Kim D.H., Usui T., Aoyagi K., Tatsuta T., Aoki K., Yanagihara K.,
RA Tamura M., Mizushima H., Sakamoto H., Ogawa K., Ohki M., Shiroishi T.,
RA Yoshida T., Sasaki H.;
RT "GASDERMIN, suppressed frequently in gastric cancer, is a target of LMO1 in
RT TGF-beta-dependent apoptotic signalling.";
RL Oncogene 26:6488-6498(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Wang Y.-G.;
RT "FKSG9, a gastric cancer-related gene, is localized to human chromosome
RT 17.";
RL Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-128.
RC TISSUE=Tongue;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS LEU-128 AND ASN-314.
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 TISSUE SPECIFICITY.
RX PubMed=10967128; DOI=10.1007/s003350010138;
RA Saeki N., Kuwahara Y., Sasaki H., Satoh H., Shiroishi T.;
RT "Gasdermin (Gsdm) localizing to mouse chromosome 11 is predominantly
RT expressed in upper gastrointestinal tract but significantly suppressed in
RT human gastric cancer cells.";
RL Mamm. Genome 11:718-724(2000).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=19051310; DOI=10.1002/gcc.20636;
RA Saeki N., Usui T., Aoyagi K., Kim D.H., Sato M., Mabuchi T., Yanagihara K.,
RA Ogawa K., Sakamoto H., Yoshida T., Sasaki H.;
RT "Distinctive expression and function of four GSDM family genes (GSDMA-D) in
RT normal and malignant upper gastrointestinal epithelium.";
RL Genes Chromosomes Cancer 48:261-271(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [9]
RP FUNCTION, AND MUTAGENESIS OF LEU-260; TYR-334 AND ALA-338.
RX PubMed=27281216; DOI=10.1038/nature18590;
RA Ding J., Wang K., Liu W., She Y., Sun Q., Shi J., Sun H., Wang D.C.,
RA Shao F.;
RT "Pore-forming activity and structural autoinhibition of the gasdermin
RT family.";
RL Nature 535:111-116(2016).
CC -!- FUNCTION: [Gasdermin-A]: This form constitutes the precursor of the
CC pore-forming protein: upon cleavage, the released N-terminal moiety
CC (Gasdermin-A, N-terminal) binds to membranes and forms pores,
CC triggering cell death. {ECO:0000269|PubMed:27281216}.
CC -!- FUNCTION: [Gasdermin-A, N-terminal]: Pore-forming protein that causes
CC membrane permeabilization and pyroptosis (PubMed:17471240,
CC PubMed:27281216). Released upon cleavage in vitro of genetically
CC engineered GSDMA, and binds to membrane inner leaflet lipids
CC (PubMed:27281216). Homooligomerizes within the membrane and forms pores
CC of 10-15 nanometers (nm) of inner diameter, triggering pyroptosis
CC (PubMed:27281216). Binds to membrane inner leaflet lipids, such as
CC phosphatidylinositol (4,5)-bisphosphate (PubMed:27281216). The
CC functional mechanisms and physiological proteases that cleave and
CC activate this pore-forming protein are unknown (PubMed:27281216).
CC {ECO:0000269|PubMed:17471240, ECO:0000269|PubMed:27281216}.
CC -!- ACTIVITY REGULATION: [Gasdermin-A]: The full-length protein before
CC cleavage is inactive: intramolecular interactions between N- and C-
CC terminal domains mediate autoinhibition in the absence of activation
CC signal. The intrinsic pyroptosis-inducing activity is carried by the
CC released N-terminal moiety (Gasdermin-A, N-terminal).
CC {ECO:0000250|UniProtKB:Q5Y4Y6}.
CC -!- SUBUNIT: [Gasdermin-A, N-terminal]: Homooligomer; homooligomeric ring-
CC shaped pore complex containing 27-28 subunits when inserted in the
CC membrane. {ECO:0000250|UniProtKB:Q5Y4Y6}.
CC -!- INTERACTION:
CC Q96QA5; P02654: APOC1; NbExp=3; IntAct=EBI-11320924, EBI-1220105;
CC Q96QA5; P55056: APOC4; NbExp=3; IntAct=EBI-11320924, EBI-18302142;
CC -!- SUBCELLULAR LOCATION: [Gasdermin-A]: Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:17471240}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q5Y4Y6}.
CC -!- SUBCELLULAR LOCATION: [Gasdermin-A, N-terminal]: Cell membrane
CC {ECO:0000250|UniProtKB:Q5Y4Y6}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q5Y4Y6}.
CC -!- TISSUE SPECIFICITY: Expressed predominantly in the gastrointestinal
CC tract and, at a lower level, in the skin. Also detected in mammary
CC gland. In the gastrointestinal tract, mainly expressed in
CC differentiated cells, including the differentiated cell layer of
CC esophagus and mucus-secreting pit cells of the gastric epithelium.
CC Down-regulateded in gastric cancer cells. {ECO:0000269|PubMed:10967128,
CC ECO:0000269|PubMed:17471240, ECO:0000269|PubMed:19051310}.
CC -!- DOMAIN: Intramolecular interactions between N- and C-terminal domains
CC are important for autoinhibition in the absence of activation signal.
CC The intrinsic pyroptosis-inducing activity is carried by the N-terminal
CC domain. {ECO:0000250|UniProtKB:Q5Y4Y6}.
CC -!- PTM: Cleavage relieves autoinhibition by releasing the N-terminal
CC moiety (Gasdermin-A, N-terminal) that initiates pyroptosis.
CC {ECO:0000250|UniProtKB:P57764}.
CC -!- SIMILARITY: Belongs to the gasdermin family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/GSDMAID45650ch17q21.html";
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DR EMBL; AB093591; BAC75636.1; -; mRNA.
DR EMBL; AF307953; AAL14426.1; -; mRNA.
DR EMBL; AK096439; BAC04790.1; -; mRNA.
DR EMBL; AC090844; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC109197; AAI09198.1; -; mRNA.
DR CCDS; CCDS45669.1; -.
DR RefSeq; NP_835465.2; NM_178171.4.
DR RefSeq; XP_006721895.1; XM_006721832.2.
DR AlphaFoldDB; Q96QA5; -.
DR SMR; Q96QA5; -.
DR BioGRID; 129762; 116.
DR IntAct; Q96QA5; 12.
DR MINT; Q96QA5; -.
DR STRING; 9606.ENSP00000301659; -.
DR TCDB; 1.C.123.1.2; the pore-forming gasdermin (gasdermin) family.
DR GlyGen; Q96QA5; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96QA5; -.
DR PhosphoSitePlus; Q96QA5; -.
DR BioMuta; GSDMA; -.
DR DMDM; 296439478; -.
DR EPD; Q96QA5; -.
DR MassIVE; Q96QA5; -.
DR PaxDb; Q96QA5; -.
DR PeptideAtlas; Q96QA5; -.
DR PRIDE; Q96QA5; -.
DR ProteomicsDB; 77846; -.
DR Antibodypedia; 7880; 113 antibodies from 20 providers.
DR DNASU; 284110; -.
DR Ensembl; ENST00000301659.9; ENSP00000301659.4; ENSG00000167914.12.
DR Ensembl; ENST00000635792.1; ENSP00000490739.1; ENSG00000167914.12.
DR GeneID; 284110; -.
DR KEGG; hsa:284110; -.
DR MANE-Select; ENST00000301659.9; ENSP00000301659.4; NM_178171.5; NP_835465.2.
DR UCSC; uc002htl.1; human.
DR CTD; 284110; -.
DR DisGeNET; 284110; -.
DR GeneCards; GSDMA; -.
DR HGNC; HGNC:13311; GSDMA.
DR HPA; ENSG00000167914; Tissue enriched (skin).
DR MIM; 611218; gene.
DR neXtProt; NX_Q96QA5; -.
DR OpenTargets; ENSG00000167914; -.
DR PharmGKB; PA162390274; -.
DR VEuPathDB; HostDB:ENSG00000167914; -.
DR eggNOG; ENOG502S0IQ; Eukaryota.
DR GeneTree; ENSGT00950000183140; -.
DR HOGENOM; CLU_040752_0_0_1; -.
DR InParanoid; Q96QA5; -.
DR OMA; HICNDSM; -.
DR OrthoDB; 747086at2759; -.
DR PhylomeDB; Q96QA5; -.
DR TreeFam; TF331886; -.
DR PathwayCommons; Q96QA5; -.
DR SignaLink; Q96QA5; -.
DR BioGRID-ORCS; 284110; 213 hits in 1062 CRISPR screens.
DR GenomeRNAi; 284110; -.
DR Pharos; Q96QA5; Tbio.
DR PRO; PR:Q96QA5; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q96QA5; protein.
DR Bgee; ENSG00000167914; Expressed in skin of leg and 79 other tissues.
DR ExpressionAtlas; Q96QA5; baseline and differential.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IBA:GO_Central.
DR GO; GO:0070273; F:phosphatidylinositol-4-phosphate binding; IBA:GO_Central.
DR GO; GO:0001786; F:phosphatidylserine binding; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IDA:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IBA:GO_Central.
DR GO; GO:0070269; P:pyroptosis; IBA:GO_Central.
DR InterPro; IPR007677; Gasdermin.
DR InterPro; IPR040460; Gasdermin_pore.
DR InterPro; IPR041263; Gasdermin_PUB.
DR PANTHER; PTHR16399; PTHR16399; 1.
DR Pfam; PF04598; Gasdermin; 1.
DR Pfam; PF17708; Gasdermin_C; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cytoplasm; Membrane; Necrosis; Reference proteome;
KW Transmembrane; Transmembrane beta strand.
FT CHAIN 1..445
FT /note="Gasdermin-A"
FT /id="PRO_0000148173"
FT CHAIN 1..?
FT /note="Gasdermin-A, N-terminal"
FT /evidence="ECO:0000305"
FT /id="PRO_0000451664"
FT CHAIN ?..445
FT /note="Gasdermin-A, C-terminal"
FT /evidence="ECO:0000305"
FT /id="PRO_0000451665"
FT TRANSMEM 78..95
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:Q5Y4Y6"
FT TRANSMEM 99..120
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:Q5Y4Y6"
FT TRANSMEM 163..179
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:Q5Y4Y6"
FT TRANSMEM 183..197
FT /note="Beta stranded"
FT /evidence="ECO:0000250|UniProtKB:Q5Y4Y6"
FT REGION 1..251
FT /note="Triggers pyroptosis"
FT /evidence="ECO:0000269|PubMed:27281216"
FT BINDING 9..13
FT /ligand="a cardiolipin"
FT /ligand_id="ChEBI:CHEBI:62237"
FT /evidence="ECO:0000250|UniProtKB:Q5Y4Y6"
FT VARIANT 18
FT /note="R -> Q (in dbSNP:rs3894194)"
FT /id="VAR_035010"
FT VARIANT 128
FT /note="V -> L (in dbSNP:rs7212938)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17471240"
FT /id="VAR_035011"
FT VARIANT 130
FT /note="E -> K (in dbSNP:rs7212944)"
FT /evidence="ECO:0000269|PubMed:17471240"
FT /id="VAR_035012"
FT VARIANT 314
FT /note="T -> N (in dbSNP:rs56030650)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_062005"
FT MUTAGEN 260
FT /note="L->D: Spontaneous pyroptosis-inducing activity."
FT /evidence="ECO:0000269|PubMed:27281216"
FT MUTAGEN 334
FT /note="Y->D: Spontaneous pyroptosis-inducing activity."
FT /evidence="ECO:0000269|PubMed:27281216"
FT MUTAGEN 338
FT /note="A->D: Spontaneous pyroptosis-inducing activity."
FT /evidence="ECO:0000269|PubMed:27281216"
FT CONFLICT 131
FT /note="R -> RR (in Ref. 2; AAL14426)"
FT /evidence="ECO:0000305"
FT CONFLICT 181..186
FT /note="APLGLQ -> LPIGAT (in Ref. 2; AAL14426)"
FT /evidence="ECO:0000305"
FT CONFLICT 235..242
FT /note="EKSGEEKV -> GKPGEGKF (in Ref. 2; AAL14426)"
FT /evidence="ECO:0000305"
FT CONFLICT 252..253
FT /note="DV -> EM (in Ref. 2; AAL14426)"
FT /evidence="ECO:0000305"
FT CONFLICT 367..368
FT /note="ES -> RG (in Ref. 2; AAL14426)"
FT /evidence="ECO:0000305"
FT CONFLICT 437
FT /note="L -> H (in Ref. 3; BAC04790)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 445 AA; 49365 MW; FC745B63B9C40BCF CRC64;
MTMFENVTRA LARQLNPRGD LTPLDSLIDF KRFHPFCLVL RKRKSTLFWG ARYVRTDYTL
LDVLEPGSSP SDPTDTGNFG FKNMLDTRVE GDVDVPKTVK VKGTAGLSQN STLEVQTLSV
APKALETVQE RKLAADHPFL KEMQDQGENL YVVMEVVETV QEVTLERAGK AEACFSLPFF
APLGLQGSIN HKEAVTIPKG CVLAFRVRQL MVKGKDEWDI PHICNDNMQT FPPGEKSGEE
KVILIQASDV GDVHEGFRTL KEEVQRETQQ VEKLSRVGQS SLLSSLSKLL GKKKELQDLE
LALEGALDKG HEVTLEALPK DVLLSKEAVG AILYFVGALT ELSEAQQKLL VKSMEKKILP
VQLKLVESTM EQNFLLDKEG VFPLQPELLS SLGDEELTLT EALVGLSGLE VQRSGPQYMW
DPDTLPRLCA LYAGLSLLQQ LTKAS
