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Protein

Gasdermin-D

Gene

Gsdmdc1

Organism
Mus musculus (Mouse)
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:26611636, PubMed:26375259, PubMed:26375003, PubMed:27418190, PubMed:27385778, PubMed:27383986). After cleavage, moves to the plasma membrane where it strongly binds to membrane 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)-trisphosphate, and more weakly to phosphatidic acid and phosphatidylserine. Homooligomerizes within the membrane and forms pores of 10 - 15 nanometers (nm) of inner diameter, allowing the release of mature IL1B and triggering pyroptosis. 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. Under cell culture conditions, also active against intracellular bacteria, such as Listeria monocytogenes. Strongly binds to bacterial and mitochondrial lipids, including cardiolipin. Does not bind to phosphatidylethanolamine or phosphatidylcholine (PubMed:27383986).6 Publications

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processImmunity, Inflammatory response, Innate immunity, Necrosis

Enzyme and pathway databases

ReactomeiR-MMU-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-terminal
Short name:
GSDMD-NT1 Publication
Gasdermin-D, C-terminal
Short name:
GSDMD-CT1 Publication
Gene namesi
Name:Gsdmdc1
Synonyms:Gsdmd
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:1916396 Gsdmd

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

Disruption phenotypei

Knockout mice are born at the expected Mendelian rate and do not exhibit any overt phenotype in normal housing conditions. The gastrointestinal tract develops normally. They are however resistant to LPS-induced lethal septic shock. Primary bone marrow-derived macrophages fail to undergo pyroptosis in response to canonical (acting via CASP1), as well as to non-canonical (acting via CASP4) inflammasome activators. CASP1-mediated IL1B release is also impaired, but not CASP1 autoprocessing, nor IL1B maturation.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi39C → A: Loss of oligomerization of Gasdermin-D, N-terminal. 1 Publication1
Mutagenesisi57C → A: No effect on oligomerization. 1 Publication1
Mutagenesisi77C → A: No effect on oligomerization. 1 Publication1
Mutagenesisi105I → N: Loss of cytosolic LPS-induced IL1B release and pyroptosis in bone marrow-derived macrophages. No effect on protein expression. No effect on cleavage by CASP4. 1 Publication1
Mutagenesisi122C → A: No effect on oligomerization. 1 Publication1
Mutagenesisi138R → A or S: Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-146; A-152 and A-154. Partial loss of homooligomerization and pyroptosis; when associated with A-146. 1 Publication1
Mutagenesisi146K → A: Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-138 or with S-138; A-152 and A-154. Partial loss of homooligomerization and pyroptosis; when associated with A-138, with A-152 or with A-152 and A-154. 1 Publication1
Mutagenesisi152R → A: Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-138 or with S-138; A-146 and A-154. Partial loss of homooligomerization and pyroptosis; when associated with A-146 or with A-154, or with A-146 and A-154. 1 Publication1
Mutagenesisi154R → A: Complete loss of homooligomerization, lipid-binding, relocalization of Gasdermin-D, N-terminal to the plasma membrane and pyroptosis, as well as loss of bactericidal activity; when associated with A-138 or with S-138; A-146 and A-152. Partial loss of homooligomerization and pyroptosis; when associated with A-152 or with A-146 and A-152. 1 Publication1
Mutagenesisi192C → A: Loss of oligomerization of Gasdermin-D, N-terminal. 1 Publication1
Mutagenesisi237K → A: No effect on pyroptosis; when associated with A-239 or with A-239; A-248 and A-249. 1 Publication1
Mutagenesisi239R → A: No effect on pyroptosis; when associated with A-237 or with A-237; A-248 and A-249. 1 Publication1
Mutagenesisi248R → A: No effect on pyroptosis; when associated with A-237; A-239 and A-249. 1 Publication1
Mutagenesisi249K → A: No effect on pyroptosis; when associated with A-237; A-239 and A-248. 1 Publication1
Mutagenesisi265C → A: No effect on oligomerization. 1 Publication1
Mutagenesisi276D → A or N: Loss of CASP1-induced cleavage, pyroptosis and IL1B release. 2 Publications1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001481761 – 487Gasdermin-DAdd BLAST487
ChainiPRO_00004375281 – 276Gasdermin-D, N-terminal1 PublicationAdd BLAST276
ChainiPRO_0000437529277 – 487Gasdermin-D, C-terminal1 PublicationAdd BLAST211

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei38PhosphotyrosineBy similarity1

Post-translational modificationi

Cleavage at Asp-276 by CASP1 (mature and uncleaved precursor forms) or CASP4 relieves autoinhibition and is sufficient to initiate pyroptosis (PubMed:26375259, PubMed:26611636). Cleavage at Asp-88 by CASP3 (By similarity).By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei88 – 89Cleavage; by CASP3By similarity2
Sitei276 – 277Cleavage; by inflammatory caspases CASP1 and CASP41 Publication2

Keywords - PTMi

Disulfide bond, Phosphoprotein

Proteomic databases

EPDiQ9D8T2
MaxQBiQ9D8T2
PaxDbiQ9D8T2
PeptideAtlasiQ9D8T2
PRIDEiQ9D8T2

PTM databases

iPTMnetiQ9D8T2
PhosphoSitePlusiQ9D8T2

Expressioni

Developmental stagei

Expression starts at 8.5 dpc and increases from 13.5 dpc on. Still detected after birth.1 Publication

Gene expression databases

BgeeiENSMUSG00000022575 Expressed in 144 organ(s), highest expression level in intestine
CleanExiMM_GSDMD
GenevisibleiQ9D8T2 MM

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 (PubMed:26611636). Gasdermin-D, N-terminal forms disulfide-linked homooligomers (16-mers) in a Ca(+2)-independent manner. Oligomerization occurs in the presence of membranes; remains monomeric in the cytosol (PubMed:27383986).2 Publications

Protein-protein interaction databases

DIPiDIP-61777N
IntActiQ9D8T2, 1 interactor
STRINGi10090.ENSMUSP00000023238

Structurei

Secondary structure

1487
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9D8T2
SMRiQ9D8T2
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.3 Publications

Sequence similaritiesi

Belongs to the gasdermin family.Curated

Phylogenomic databases

eggNOGiENOG410IKA4 Eukaryota
ENOG4111D9N LUCA
GeneTreeiENSGT00530000063218
HOGENOMiHOG000082450
HOVERGENiHBG099862
InParanoidiQ9D8T2
KOiK20917
OMAiQGPTCAL
OrthoDBiEOG091G09ST
PhylomeDBiQ9D8T2
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 2 potential isoforms that are computationally mapped.Show allAlign All

Q9D8T2-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MPSAFEKVVK NVIKEVSGSR GDLIPVDSLR NSTSFRPYCL LNRKFSSSRF
60 70 80 90 100
WKPRYSCVNL SIKDILEPSA PEPEPECFGS FKVSDVVDGN IQGRVMLSGM
110 120 130 140 150
GEGKISGGAA VSDSSSASMN VCILRVTQKT WETMQHERHL QQPENKILQQ
160 170 180 190 200
LRSRGDDLFV VTEVLQTKEE VQITEVHSQE GSGQFTLPGA LCLKGEGKGH
210 220 230 240 250
QSRKKMVTIP AGSILAFRVA QLLIGSKWDI LLVSDEKQRT FEPSSGDRKA
260 270 280 290 300
VGQRHHGLNV LAALCSIGKQ LSLLSDGIDE EELIEAADFQ GLYAEVKACS
310 320 330 340 350
SELESLEMEL RQQILVNIGK ILQDQPSMEA LEASLGQGLC SGGQVEPLDG
360 370 380 390 400
PAGCILECLV LDSGELVPEL AAPIFYLLGA LAVLSETQQQ LLAKALETTV
410 420 430 440 450
LSKQLELVKH VLEQSTPWQE QSSVSLPTVL LGDCWDEKNP TWVLLEECGL
460 470 480
RLQVESPQVH WEPTSLIPTS ALYASLFLLS SLGQKPC
Length:487
Mass (Da):53,238
Last modified:June 1, 2001 - v1
Checksum:i6702C95B0F92BC49
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A0A2R8W727A0A2R8W727_MOUSE
Gasdermin D
Gsdmd
57Annotation score:
A0A2R8VKQ7A0A2R8VKQ7_MOUSE
Gasdermin D
Gsdmd
263Annotation score:

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK007710 mRNA Translation: BAB25204.1
AK165858 mRNA Translation: BAE38418.1
AK171294 mRNA Translation: BAE42374.1
BC029813 mRNA Translation: AAH29813.1
CCDSiCCDS27551.1
RefSeqiNP_081236.1, NM_026960.4
UniGeneiMm.27385

Genome annotation databases

EnsembliENSMUST00000023238; ENSMUSP00000023238; ENSMUSG00000022575
GeneIDi69146
KEGGimmu:69146
UCSCiuc007whh.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK007710 mRNA Translation: BAB25204.1
AK165858 mRNA Translation: BAE38418.1
AK171294 mRNA Translation: BAE42374.1
BC029813 mRNA Translation: AAH29813.1
CCDSiCCDS27551.1
RefSeqiNP_081236.1, NM_026960.4
UniGeneiMm.27385

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
6AO3X-ray1.76A/B/C/D277-487[»]
ProteinModelPortaliQ9D8T2
SMRiQ9D8T2
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-61777N
IntActiQ9D8T2, 1 interactor
STRINGi10090.ENSMUSP00000023238

PTM databases

iPTMnetiQ9D8T2
PhosphoSitePlusiQ9D8T2

Proteomic databases

EPDiQ9D8T2
MaxQBiQ9D8T2
PaxDbiQ9D8T2
PeptideAtlasiQ9D8T2
PRIDEiQ9D8T2

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000023238; ENSMUSP00000023238; ENSMUSG00000022575
GeneIDi69146
KEGGimmu:69146
UCSCiuc007whh.1 mouse

Organism-specific databases

CTDi79792
MGIiMGI:1916396 Gsdmd

Phylogenomic databases

eggNOGiENOG410IKA4 Eukaryota
ENOG4111D9N LUCA
GeneTreeiENSGT00530000063218
HOGENOMiHOG000082450
HOVERGENiHBG099862
InParanoidiQ9D8T2
KOiK20917
OMAiQGPTCAL
OrthoDBiEOG091G09ST
PhylomeDBiQ9D8T2
TreeFamiTF331886

Enzyme and pathway databases

ReactomeiR-MMU-6798695 Neutrophil degranulation

Miscellaneous databases

PROiPR:Q9D8T2
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000022575 Expressed in 144 organ(s), highest expression level in intestine
CleanExiMM_GSDMD
GenevisibleiQ9D8T2 MM

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_MOUSE
AccessioniPrimary (citable) accession number: Q9D8T2
Secondary accession number(s): Q3TBD9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: June 1, 2001
Last modified: November 7, 2018
This is version 109 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

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

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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