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Protein

Gasdermin-D

Gene

GSDMD

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

Keywordsi

Biological processImmunity, Inflammatory response, Innate immunity, Necrosis

Enzyme and pathway databases

ReactomeiR-HSA-6798695 Neutrophil degranulation

Protein family/group databases

TCDBi1.C.123.1.1 the pore-forming gasdermin (gasdermin) family

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

EuPathDBiHostDB:ENSG00000104518.10
HGNCiHGNC:25697 GSDMD
MIMi617042 gene
neXtProtiNX_P57764

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Inflammasome, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi15E → K: No spontaneous pyroptosis-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 pyroptosis-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 pyroptosis-inducing activity. 1 Publication1
Mutagenesisi373Y → D: Spontaneous pyroptosis-inducing activity. 1 Publication1
Mutagenesisi377A → D: Spontaneous pyroptosis-inducing activity. 1 Publication1

Organism-specific databases

DisGeNETi79792
OpenTargetsiENSG00000104518
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 (PubMed:26375003). Cleavage at Asp-87 by CASP3 (PubMed:28045099).2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei87 – 88Cleavage; by CASP31 Publication2
Sitei275 – 276Cleavage; by inflammatory caspases CASP1 and CASP41 Publication2

Keywords - PTMi

Disulfide bond, Phosphoprotein

Proteomic databases

EPDiP57764
MaxQBiP57764
PaxDbiP57764
PeptideAtlasiP57764
PRIDEiP57764
ProteomicsDBi57029

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 Expressed in 171 organ(s), highest expression level in spleen
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, 13 interactors
STRINGi9606.ENSP00000262580

Structurei

Secondary structure

1484
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP57764
SMRiP57764
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
KOiK20917
PhylomeDBiP57764
TreeFamiTF331886

Family and domain databases

InterProiView protein in InterPro
IPR007677 Gasdermin
PANTHERiPTHR16399 PTHR16399, 1 hit
PfamiView protein in Pfam
PF04598 Gasdermin, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

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

This entry has 1 described isoform and 7 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 7 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G3V1A6G3V1A6_HUMAN
Gasdermin domain containing 1, isof...
GSDMD GSDMDC1, hCG_32063
532Annotation score:
E9PIB2E9PIB2_HUMAN
Gasdermin-D
GSDMD
277Annotation score:
E9PQ48E9PQ48_HUMAN
Gasdermin-D
GSDMD
114Annotation score:
E9PQR9E9PQR9_HUMAN
Gasdermin-D
GSDMD
164Annotation score:
E9PRF1E9PRF1_HUMAN
Gasdermin-D
GSDMD
48Annotation score:
E9PNZ0E9PNZ0_HUMAN
Gasdermin-D
GSDMD
153Annotation score:
H0YDB0H0YDB0_HUMAN
Gasdermin-D
GSDMD
231Annotation score:

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

Similar proteinsi

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

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5NH1X-ray2.04A278-484[»]
5WQTX-ray2.64A/B276-484[»]
6AO4X-ray2.90A277-484[»]
ProteinModelPortaliP57764
SMRiP57764
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi122891, 1 interactor
DIPiDIP-61775N
IntActiP57764, 13 interactors
STRINGi9606.ENSP00000262580

Protein family/group databases

TCDBi1.C.123.1.1 the pore-forming gasdermin (gasdermin) family

PTM databases

iPTMnetiP57764
PhosphoSitePlusiP57764

Polymorphism and mutation databases

BioMutaiGSDMD
DMDMi13124058

Proteomic databases

EPDiP57764
MaxQBiP57764
PaxDbiP57764
PeptideAtlasiP57764
PRIDEiP57764
ProteomicsDBi57029

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
EuPathDBiHostDB:ENSG00000104518.10
GeneCardsiGSDMD
HGNCiHGNC:25697 GSDMD
HPAiCAB004656
HPA044487
MIMi617042 gene
neXtProtiNX_P57764
OpenTargetsiENSG00000104518
PharmGKBiPA162390357
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IKA4 Eukaryota
ENOG4111D9N LUCA
GeneTreeiENSGT00530000063218
HOGENOMiHOG000082450
HOVERGENiHBG099862
InParanoidiP57764
KOiK20917
PhylomeDBiP57764
TreeFamiTF331886

Enzyme and pathway databases

ReactomeiR-HSA-6798695 Neutrophil degranulation

Miscellaneous databases

ChiTaRSiGSDMD human
GenomeRNAii79792
PROiPR:P57764
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000104518 Expressed in 171 organ(s), highest expression level in spleen
CleanExiHS_GSDMD
ExpressionAtlasiP57764 baseline and differential
GenevisibleiP57764 HS

Family and domain databases

InterProiView protein in InterPro
IPR007677 Gasdermin
PANTHERiPTHR16399 PTHR16399, 1 hit
PfamiView protein in Pfam
PF04598 Gasdermin, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiGSDMD_HUMAN
AccessioniPrimary (citable) accession number: P57764
Secondary accession number(s): A8K702, D3DWJ9, Q96Q98
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 21, 2001
Last sequence update: February 21, 2001
Last modified: October 10, 2018
This is version 138 of the entry and version 1 of the sequence. See 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

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

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