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Protein

Gasdermin-D

Gene

GSDMD

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Gasdermin-D, N-terminal: Promotes pyroptosis in response to microbial infection and danger signals. Produced by the cleavage of gasdermin-D by inflammatory caspases CASP1 or CASP4 in response to canonical, as well as non-canonical (such as cytosolic LPS) inflammasome activators (PubMed:26375003, PubMed:26375259, PubMed:27418190). After cleavage, moves to the plasma membrane where it strongly binds to inner leaflet lipids, including monophosphorylated phosphatidylinositols, such as phosphatidylinositol 4-phosphate, bisphosphorylated phosphatidylinositols, such as phosphatidylinositol (4,5)-bisphosphate, as well as phosphatidylinositol (3,4,5)-bisphosphate, and more weakly to phosphatidic acid and phosphatidylserine (PubMed:27281216). Homooligomerizes within the membrane and forms pores of 10 - 15 nanometers (nm) of inner diameter, possibly allowing the release of mature IL1B and triggering pyroptosis (PubMed:27418190, PubMed:27281216). Exhibits bactericidal activity. Gasdermin-D, N-terminal released from pyroptotic cells into the extracellular milieu rapidly binds to and kills both Gram-negative and Gram-positive bacteria, without harming neighboring mammalian cells, as it does not disrupt the plasma membrane from the outside due to lipid-binding specificity (PubMed:27281216). Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes (By similarity). Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to unphosphorylated phosphatidylinositol, phosphatidylethanolamine nor phosphatidylcholine (PubMed:27281216).By similarity4 Publications

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity, Necrosis

Enzyme and pathway databases

BioCyciZFISH:ENSG00000104518-MONOMER.
ReactomeiR-HSA-6798695. Neutrophil degranulation.

Names & Taxonomyi

Protein namesi
Recommended name:
Gasdermin-D
Alternative name(s):
Gasdermin domain-containing protein 1
Cleaved into the following 2 chains:
Gasdermin-D, N-terminalBy similarity
Short name:
GSDMD-NT
Gasdermin-D, C-terminalBy similarity
Short name:
GSDMD-CT
Gene namesi
Name:GSDMD
Synonyms:DFNA5L, GSDMDC1
ORF Names:FKSG10
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

HGNCiHGNC:25697. GSDMD.

Subcellular locationi

Gasdermin-D :
  • Cytoplasmcytosol 1 Publication
  • Inflammasome By similarity

  • Note: In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor.By similarity
Gasdermin-D, N-terminal :
  • Cell membrane By similarity1 Publication
  • Secreted By similarity

  • Note: Released in the extracellular milieu following pyroptosis.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Inflammasome, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi15E → K: No spontaneous pyropoptis-inducing activity; when associated with D-192. 1 Publication1
Mutagenesisi104I → N: Decreased effectiveness in pore formation and pyroptosis induction. No effect on cleavage by CASP1. 1 Publication1
Mutagenesisi192L → D: Decreased induction of pyroptosis and defects in liposome-binding. No spontaneous pyropoptis-inducing activity; when associated with K-15. 1 Publication1
Mutagenesisi275D → A: Loss of cleavage by CASP1 and CASP4 and of LPS-induced pyroptosis. 1 Publication1
Mutagenesisi290L → D: Spontaneous pyropoptis-inducing activity. 1 Publication1
Mutagenesisi373Y → D: Spontaneous pyropoptis-inducing activity. 1 Publication1
Mutagenesisi377A → D: Spontaneous pyropoptis-inducing activity. 1 Publication1

Organism-specific databases

DisGeNETi79792.
OpenTargetsiENSG00000104518.
ENSG00000278718.
PharmGKBiPA162390357.

Polymorphism and mutation databases

BioMutaiGSDMD.
DMDMi13124058.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001481751 – 484Gasdermin-DAdd BLAST484
ChainiPRO_00004375261 – 275Gasdermin-D, N-terminalBy similarityAdd BLAST275
ChainiPRO_0000437527276 – 484Gasdermin-D, C-terminalBy similarityAdd BLAST209

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei37PhosphotyrosineCombined sources1
Modified residuei158PhosphotyrosineCombined sources1
Modified residuei185PhosphoserineCombined sources1

Post-translational modificationi

Cleavage at Asp-275 by CASP1 (mature and uncleaved precursor forms) or CASP4 relieves autoinhibition and is sufficient to initiate pyroptosis.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei275 – 276Cleavage; by inflammatory caspases CASP1 and CASP41 Publication2

Keywords - PTMi

Disulfide bond, Phosphoprotein

Proteomic databases

EPDiP57764.
MaxQBiP57764.
PaxDbiA8K702.
P57764.
PeptideAtlasiP57764.
PRIDEiP57764.

PTM databases

iPTMnetiP57764.
PhosphoSitePlusiP57764.

Expressioni

Tissue specificityi

Expressed in the suprabasal cells of esophagus, as well as in the isthmus/neck, pit, and gland of the stomach, suggesting preferential expression in differentiating cells.1 Publication

Gene expression databases

BgeeiENSG00000104518.
CleanExiHS_GSDMD.
ExpressionAtlasiP57764. baseline and differential.
GenevisibleiP57764. HS.

Organism-specific databases

HPAiCAB004656.
HPA044487.

Interactioni

Subunit structurei

In response to a canonical inflammasome stimulus, such as nigericin, recruited to NLRP3 inflammasone with similar kinetics to that of uncleaved CASP1 precursor. Although this recruitment is also observed in the absence of PYCARD, it is more efficient in its presence (By similarity). Gasdermin-D, N-terminal forms disulfide-linked homooligomers (16-mers) in a Ca(+2)-independent manner. Oligomerization occurs in the presence of membranes; cytosolic Gasdermin-D, N-terminal remains monomeric (PubMed:27281216).By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
KCTD6Q8NC695EBI-2798865,EBI-2511344

Protein-protein interaction databases

BioGridi122891. 1 interactor.
DIPiDIP-61775N.
IntActiP57764. 6 interactors.
STRINGi9606.ENSP00000262580.

Structurei

3D structure databases

ProteinModelPortaliP57764.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domaini

Intramolecular interactions between N- and C-terminal domains may be important for autoinhibition in the absence of cleavage by inflammatory caspases CASP1 or CASP4. The intrinsic pyroptosis-inducing activity is carried by gasdermin-D, N-terminal, that is released upon cleavage by inflammatory caspases.1 Publication

Sequence similaritiesi

Belongs to the gasdermin family.Curated

Phylogenomic databases

eggNOGiENOG410IKA4. Eukaryota.
ENOG4111D9N. LUCA.
GeneTreeiENSGT00530000063218.
HOGENOMiHOG000082450.
HOVERGENiHBG099862.
InParanoidiP57764.
PhylomeDBiP57764.
TreeFamiTF331886.

Family and domain databases

InterProiIPR007677. Gasdermin.
[Graphical view]
PANTHERiPTHR16399. PTHR16399. 1 hit.
PfamiPF04598. Gasdermin. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P57764-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGSAFERVVR RVVQELDHGG EFIPVTSLQS STGFQPYCLV VRKPSSSWFW
60 70 80 90 100
KPRYKCVNLS IKDILEPDAA EPDVQRGRSF HFYDAMDGQI QGSVELAAPG
110 120 130 140 150
QAKIAGGAAV SDSSSTSMNV YSLSVDPNTW QTLLHERHLR QPEHKVLQQL
160 170 180 190 200
RSRGDNVYVV TEVLQTQKEV EVTRTHKREG SGRFSLPGAT CLQGEGQGHL
210 220 230 240 250
SQKKTVTIPS GSTLAFRVAQ LVIDSDLDVL LFPDKKQRTF QPPATGHKRS
260 270 280 290 300
TSEGAWPQLP SGLSMMRCLH NFLTDGVPAE GAFTEDFQGL RAEVETISKE
310 320 330 340 350
LELLDRELCQ LLLEGLEGVL RDQLALRALE EALEQGQSLG PVEPLDGPAG
360 370 380 390 400
AVLECLVLSS GMLVPELAIP VVYLLGALTM LSETQHKLLA EALESQTLLG
410 420 430 440 450
PLELVGSLLE QSAPWQERST MSLPPGLLGN SWGEGAPAWV LLDECGLELG
460 470 480
EDTPHVCWEP QAQGRMCALY ASLALLSGLS QEPH
Length:484
Mass (Da):52,801
Last modified:February 21, 2001 - v1
Checksum:iF7CE8073E0C0194D
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti360 – 483SGMLV…LSQEP → PECWCRNSLSLLSTCWG in AAG22861 (Ref. 1) CuratedAdd BLAST124
Sequence conflicti386H → R in BAF84506 (PubMed:14702039).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY008304 mRNA. Translation: AAG22861.1.
AK022212 mRNA. Translation: BAB13986.1.
AK291817 mRNA. Translation: BAF84506.1.
AC067930 Genomic DNA. No translation available.
CH471162 Genomic DNA. Translation: EAW82243.1.
CH471162 Genomic DNA. Translation: EAW82245.1.
BC008904 mRNA. Translation: AAH08904.1.
BC069000 mRNA. Translation: AAH69000.1.
CCDSiCCDS34956.1.
RefSeqiNP_001159709.1. NM_001166237.1.
NP_079012.3. NM_024736.6.
UniGeneiHs.118983.

Genome annotation databases

EnsembliENST00000262580; ENSP00000262580; ENSG00000104518.
ENST00000526406; ENSP00000433209; ENSG00000104518.
ENST00000615119; ENSP00000482096; ENSG00000278718.
ENST00000631751; ENSP00000488012; ENSG00000278718.
GeneIDi79792.
KEGGihsa:79792.
UCSCiuc003yyg.4. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY008304 mRNA. Translation: AAG22861.1.
AK022212 mRNA. Translation: BAB13986.1.
AK291817 mRNA. Translation: BAF84506.1.
AC067930 Genomic DNA. No translation available.
CH471162 Genomic DNA. Translation: EAW82243.1.
CH471162 Genomic DNA. Translation: EAW82245.1.
BC008904 mRNA. Translation: AAH08904.1.
BC069000 mRNA. Translation: AAH69000.1.
CCDSiCCDS34956.1.
RefSeqiNP_001159709.1. NM_001166237.1.
NP_079012.3. NM_024736.6.
UniGeneiHs.118983.

3D structure databases

ProteinModelPortaliP57764.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi122891. 1 interactor.
DIPiDIP-61775N.
IntActiP57764. 6 interactors.
STRINGi9606.ENSP00000262580.

PTM databases

iPTMnetiP57764.
PhosphoSitePlusiP57764.

Polymorphism and mutation databases

BioMutaiGSDMD.
DMDMi13124058.

Proteomic databases

EPDiP57764.
MaxQBiP57764.
PaxDbiA8K702.
P57764.
PeptideAtlasiP57764.
PRIDEiP57764.

Protocols and materials databases

DNASUi79792.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000262580; ENSP00000262580; ENSG00000104518.
ENST00000526406; ENSP00000433209; ENSG00000104518.
ENST00000615119; ENSP00000482096; ENSG00000278718.
ENST00000631751; ENSP00000488012; ENSG00000278718.
GeneIDi79792.
KEGGihsa:79792.
UCSCiuc003yyg.4. human.

Organism-specific databases

CTDi79792.
DisGeNETi79792.
GeneCardsiGSDMD.
HGNCiHGNC:25697. GSDMD.
HPAiCAB004656.
HPA044487.
MIMi617042. gene.
neXtProtiNX_P57764.
OpenTargetsiENSG00000104518.
ENSG00000278718.
PharmGKBiPA162390357.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IKA4. Eukaryota.
ENOG4111D9N. LUCA.
GeneTreeiENSGT00530000063218.
HOGENOMiHOG000082450.
HOVERGENiHBG099862.
InParanoidiP57764.
PhylomeDBiP57764.
TreeFamiTF331886.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000104518-MONOMER.
ReactomeiR-HSA-6798695. Neutrophil degranulation.

Miscellaneous databases

ChiTaRSiGSDMD. human.
GenomeRNAii79792.
PROiP57764.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000104518.
CleanExiHS_GSDMD.
ExpressionAtlasiP57764. baseline and differential.
GenevisibleiP57764. HS.

Family and domain databases

InterProiIPR007677. Gasdermin.
[Graphical view]
PANTHERiPTHR16399. PTHR16399. 1 hit.
PfamiPF04598. Gasdermin. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGSDMD_HUMAN
AccessioniPrimary (citable) accession number: P57764
Secondary accession number(s): A8K702, D3DWJ9, Q96Q98
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 21, 2001
Last sequence update: February 21, 2001
Last modified: November 30, 2016
This is version 125 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.