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Protein

Deoxynucleoside triphosphate triphosphohydrolase SAMHD1

Gene

SAMHD1

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

Functioni

Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks (PubMed:19525956, PubMed:21613998, PubMed:21720370, PubMed:23602554, PubMed:23601106, PubMed:22056990, PubMed:24336198, PubMed:26294762, PubMed:26431200, PubMed:28229507, PubMed:28834754, PubMed:29670289). Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses, such as HIV-1: dNTPase activity reduces cellular dNTP levels to levels too low for retroviral reverse transcription to occur, blocking early-stage virus replication in dendritic and other myeloid cells (PubMed:19525956, PubMed:21613998, PubMed:21720370, PubMed:23602554, PubMed:23601106, PubMed:23364794, PubMed:25038827, PubMed:26101257, PubMed:22056990, PubMed:24336198, PubMed:28229507, PubMed:26294762, PubMed:26431200). Likewise, suppresses LINE-1 retrotransposon activity (PubMed:24035396, PubMed:29610582, PubMed:24217394). Not able to restrict infection by HIV-2 virus; because restriction activity is counteracted by HIV-2 viral protein Vpx (PubMed:21613998, PubMed:21720370). In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools (PubMed:23858451). Phosphorylation at Thr-592 acts as a switch to control dNTPase-dependent and -independent functions: it inhibits dNTPase activity and ability to restrict infection by viruses, while it promotes DNA end resection at stalled replication forks (PubMed:23602554, PubMed:23601106, PubMed:29610582, PubMed:29670289). Functions during S phase at stalled DNA replication forks to promote the resection of gapped or reversed forks: acts by stimulating the exonuclease activity of MRE11, activating the ATR-CHK1 pathway and allowing the forks to restart replication (PubMed:29670289). Its ability to promote degradation of nascent DNA at stalled replication forks is required to prevent induction of type I interferons, thereby preventing chronic inflammation (PubMed:27477283, PubMed:29670289). Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity (PubMed:29670289). Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (By similarity).By similarity20 Publications

Caution

Was intially thought to be allosterically stimulated by dGTP (PubMed:22056990, PubMed:24141705, PubMed:24217394). However, it was later shown that it is allosterically activated and regulated via the combined actions of GTP and dNTPs (dATP, dGTP, dTTP and dCTP), which bind two separate binding sites (PubMed:25288794, PubMed:25267621, PubMed:25760601).6 Publications
Phosphorylation at Thr-592 was initially thought to impair ability to restrict infection by viruses without affecting the deoxynucleoside triphosphate (dNTPase) activity (PubMed:23601106). However, it was later shown that phosphorylation reduces the stability of the homotetramer, leading to impair the dNTPase activity (PubMed:26294762, PubMed:26431200).3 Publications
Was initially thought to have 3'-5' exonuclease activity, acting on single-stranded RNA (PubMed:23364794, PubMed:25038827). A publication also reported some DNA 3'-5' exonuclease activity (PubMed:23364794). However, it was later shown that SAMHD1 does not possess DNA and/or RNA exonuclease activities and that these activities are due to contamination during the purification process that can be removed after chromatography steps (PubMed:26101257). The exonuclease activity observed was maybe due to the presence of MRE11 during the purification steps (PubMed:29670289).4 Publications

Catalytic activityi

dNTP + H2O = Deoxynucleoside + triphosphate.6 Publications

Cofactori

Zn2+5 PublicationsNote: Binds 1 zinc ion per subunit.5 Publications

Activity regulationi

Allosterically activated and regulated via the combined actions of GTP and dNTPs (dATP, dGTP, dTTP and dCTP): Allosteric site 1 binds GTP, while allosteric site 2 binds dNTP (PubMed:25288794, PubMed:25267621, PubMed:25760601). Allosteric activation promotes the formation of highly active homotetramers (PubMed:22056990, PubMed:24141705, PubMed:24217394, PubMed:25288794, PubMed:25267621, PubMed:25760601). Phosphorylation at Thr-592 impairs homotetramerization, thereby inhibiting dNTPase activity, leading to reduced ability to restrict infection by viruses (PubMed:23602554, PubMed:23601106, PubMed:26294762, PubMed:26431200, PubMed:29610582, PubMed:29670289).12 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei116GTP7 Publications1
Binding sitei119dNTP; via amide nitrogen; shared with neighboring subunit7 Publications1
Binding sitei149Substrate1 Publication1
Binding sitei164Substrate1 Publication1
Metal bindingi167Zinc; via tele nitrogen5 Publications1
Metal bindingi206Zinc; via tele nitrogen5 Publications1
Metal bindingi207Zinc5 Publications1
Binding sitei210Substrate1 Publication1
Active sitei2331 Publication1
Metal bindingi311Zinc5 Publications1
Binding sitei315Substrate1 Publication1
Binding sitei319Substrate1 Publication1
Binding sitei333dNTP7 Publications1
Binding sitei358dNTP7 Publications1
Binding sitei366Substrate1 Publication1
Binding sitei376dNTP; shared with neighboring subunit7 Publications1
Binding sitei377dNTP; shared with neighboring subunit7 Publications1
Binding sitei451GTP; shared with neighboring subunit7 Publications1
Binding sitei455GTP; shared with neighboring subunit7 Publications1
Binding sitei523dNTP7 Publications1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi137 – 145GTP7 Publications9
Nucleotide bindingi352 – 354dNTP7 Publications3

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionAllosteric enzyme, Hydrolase
Biological processAntiviral defense, DNA damage, DNA repair, DNA replication, Immunity, Innate immunity
LigandGTP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-8956319 Nucleobase catabolism
R-HSA-909733 Interferon alpha/beta signaling
SIGNORiQ9Y3Z3

Names & Taxonomyi

Protein namesi
Recommended name:
Deoxynucleoside triphosphate triphosphohydrolase SAMHD1Curated (EC:3.1.5.-6 Publications)
Short name:
dNTPaseCurated
Alternative name(s):
Dendritic cell-derived IFNG-induced protein1 Publication
Short name:
DCIP1 Publication
Monocyte protein 51 Publication
Short name:
MOP-51 Publication
SAM domain and HD domain-containing protein 1Curated
Short name:
hSAMHD11 Publication
Gene namesi
Name:SAMHD1Imported
Synonyms:MOP51 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

EuPathDBiHostDB:ENSG00000101347.8
HGNCiHGNC:15925 SAMHD1
MIMi606754 gene
neXtProtiNX_Q9Y3Z3

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

Chromosome, Nucleus

Pathology & Biotechi

Involvement in diseasei

Aicardi-Goutieres syndrome 5 (AGS5)7 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.
See also OMIM:612952
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_078239120 – 123Missing in AGS5. 1 Publication4
Natural variantiVAR_058481123H → P in AGS5; loss of oligomerization; decreased ability to restrict LINE-1 retrotransposon activity. 4 PublicationsCorresponds to variant dbSNP:rs121434520EnsemblClinVar.1
Natural variantiVAR_058482143R → C in AGS5; loss of oligomerization. 2 PublicationsCorresponds to variant dbSNP:rs387906948EnsemblClinVar.1
Natural variantiVAR_058483143R → H in AGS5; loss of oligomerization; decreased ability to restrict LINE-1 retrotransposon activity. 4 PublicationsCorresponds to variant dbSNP:rs369035155EnsemblClinVar.1
Natural variantiVAR_058484145R → Q in AGS5; loss of oligomerization; decreased ability to restrict LINE-1 retrotransposon activity. 3 PublicationsCorresponds to variant dbSNP:rs515726145EnsemblClinVar.1
Natural variantiVAR_070633167H → Y in AGS5; loss of function in defense response to virus; loss of oligomerization; decreased ability to restrict LINE-1 retrotransposon activity. 3 Publications1
Natural variantiVAR_058486209G → S in AGS5; does not affect oligomerization; decreased ability to restrict LINE-1 retrotransposon activity; does not affect localization to nucleus. 3 PublicationsCorresponds to variant dbSNP:rs121434516EnsemblClinVar.1
Natural variantiVAR_058487254M → V in AGS5; loss of function in defense response to virus; does not affect oligomerization; decreased ability to restrict LINE-1 retrotransposon activity. 4 PublicationsCorresponds to variant dbSNP:rs121434521EnsemblClinVar.1
Natural variantiVAR_070634290R → H in AGS5; loss of oligomerization; decreased ability to restrict LINE-1 retrotransposon activity. 3 PublicationsCorresponds to variant dbSNP:rs559553527Ensembl.1
Natural variantiVAR_058488369L → S in AGS5; loss of function in defense response to virus; decreased oligomerization. 2 PublicationsCorresponds to variant dbSNP:rs515726139EnsemblClinVar.1
Natural variantiVAR_058489385M → V in AGS5; loss of function in defense response to virus; loss of oligomerization. 3 PublicationsCorresponds to variant dbSNP:rs515726140EnsemblClinVar.1
Natural variantiVAR_078240448I → T in AGS5; loss of function in defense response to virus; decreased oligomerization; does not affect localization to nucleus; novel localization to the cytoplasm. 2 PublicationsCorresponds to variant dbSNP:rs774964432EnsemblClinVar.1
Natural variantiVAR_080530548 – 626Missing in AGS5; Does not affect dNTP regulation, while affecting ability to promote DNA end resection at stalled replication forks. 1 PublicationAdd BLAST79
Chilblain lupus 2 (CHBL2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade.
See also OMIM:614415

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi77L → F: Increased stability of the tetramer and increased deoxynucleoside triphosphate (dNTPase) activity; when associated with F-77 and F-80 and R-111. 1 Publication1
Mutagenesisi80C → F: Increased stability of the tetramer and increased deoxynucleoside triphosphate (dNTPase) activity; when associated with F-77 and R-111. 1 Publication1
Mutagenesisi111H → R: Increased stability of the tetramer and increased deoxynucleoside triphosphate (dNTPase) activity; when associated with F-77 and F-80. 1 Publication1
Mutagenesisi137D → A: Impairs homotetramerization and nearly abolishes dNTPase activity. 3 Publications1
Mutagenesisi142Q → E or A: Impairs homotetramerization and nearly abolishes dNTPase activity; when associated with K-145. 2 Publications1
Mutagenesisi143R → A: Abolished ability to restrict infection by viruses. 1 Publication1
Mutagenesisi145R → A: Impairs homotetramerization and nearly abolishes dNTPase activity. Abolished ability to restrict infection by viruses. 2 Publications1
Mutagenesisi145R → K: Impairs homotetramerization and nearly abolishes dNTPase activity; when associated with E-145. 1 Publication1
Mutagenesisi149Q → A: Abolished dNTPase activity without affecting homotetramerization. Abolished dNTPase activity; when associated with A-319. 2 Publications1
Mutagenesisi164R → A: Abolished ability to restrict infection by viruses. 1 Publication1
Mutagenesisi167H → A: Abolished ability to restrict infection by viruses. 1 Publication1
Mutagenesisi206 – 207HD → RN: Abolishes zinc binding and dNTPase activity. Does not affect ability to promote DNA end resection at stalled replication forks. 5 Publications2
Mutagenesisi206H → A: Abolished ability to restrict infection by viruses. 1 Publication1
Mutagenesisi207D → A: Abolished ability to restrict infection by viruses. 1 Publication1
Mutagenesisi207D → N or A: Loss of dNTPase activity. 2 Publications1
Mutagenesisi210H → A: Abolished dNTPase activity without affecting homotetramerization. 1 Publication1
Mutagenesisi215H → A: Abolished dNTPase activity without affecting homotetramerization. 1 Publication1
Mutagenesisi226R → G: Loss of function in defense response to virus. 1 Publication1
Mutagenesisi233H → A: Abolished dNTPase activity without affecting homotetramerization. Abolished ability to restrict infection by viruses. 2 Publications1
Mutagenesisi311D → A: Loss of function in defense response to virus. Loss of dNTPase activity. Does not affect oligomerization. 3 Publications1
Mutagenesisi312K → A: Abolishes dNTPase activity; when associated with A-315 and A-366. Does not affect ability to promote DNA end resection at stalled replication forks; when associated with A-315. 2 Publications1
Mutagenesisi315Y → A: Abolished ability to restrict infection by viruses. Abolishes dNTPase activity; when associated with A-312 and A-366. Does not affect ability to promote DNA end resection at stalled replication forks; when associated with A-312. 3 Publications1
Mutagenesisi319D → A: Abolishes dNTPase activity; when associated with A-149. 1 Publication1
Mutagenesisi321H → A: Abolished ability to restrict infection by viruses. 1 Publication1
Mutagenesisi330D → A: Impaired homotetramerization and slightly reduced dNTPase activity. Impaired homotetramerization and reduced dNTPase activity; when associated with A-358. 2 Publications1
Mutagenesisi333R → E: Decreases dNTPase activity. Impairs homotetramerization and nearly abolishes dNTPase activity; when associated with E-451. 2 Publications1
Mutagenesisi352R → A: Impairs homotetramerization and abolishes dNTPase activity; when associated with A-376 and A-377. 1 Publication1
Mutagenesisi358N → A: Impaired homotetramerization and slightly reduced dNTPase activity. Impaired homotetramerization and reduced dNTPase activity A-330. 2 Publications1
Mutagenesisi361D → R: Impairs homotetramerization and nearly abolishes dNTPase activity; when associated with K-364. 1 Publication1
Mutagenesisi364H → K: Impairs homotetramerization and nearly abolishes dNTPase activity; when associated with R-361. 1 Publication1
Mutagenesisi366R → A: Abolishes dNTPase activity; when associated with A-312 and A-315. 1 Publication1
Mutagenesisi370H → A: Abolishes dNTPase activity; when associated with G-374. 1 Publication1
Mutagenesisi372R → D: Abolished homotetramerization and dNTPase activity. 1 Publication1
Mutagenesisi374Y → G: Abolishes dNTPase activity; when associated with A-370. 1 Publication1
Mutagenesisi375Q → A: Abolished dNTPase activity without affecting homotetramerization. 1 Publication1
Mutagenesisi376H → A: Impairs homotetramerization and abolishes dNTPase activity; when associated with A-352 and A-377. 1
Mutagenesisi377K → A: Impairs homotetramerization and abolishes dNTPase activity; when associated with A-352 and A-376. 1
Mutagenesisi451R → E: Impairs homotetramerization and abolishes dNTPase activity. 2 Publications1
Mutagenesisi534K → A: Impairs homotetramerization and abolishes dNTPase activity; when associated with A-537 and D-540. 1 Publication1
Mutagenesisi537V → A: Impairs homotetramerization and abolishes dNTPase activity; when associated with A-534 and D-540. 1 Publication1
Mutagenesisi540L → D: Impairs homotetramerization and abolishes dNTPase activity; when associated with A-537 and A-534. 1 Publication1
Mutagenesisi548Q → A: Loss of function in defense response to virus. Does not affect oligomerization. Retains dNTPase activity. 2 Publications1
Mutagenesisi592T → A or V: Impaired ability to promote DNA end resection at stalled replication forks. Promotes dNTPase activity and ability to restrict infection by viruses. 6 Publications1
Mutagenesisi592T → E: Mimicks phosphorylation state, retains ability to promote DNA end resection at stalled replication forks. Induces large conformational changes that impair homotetramerization, leading to reduced dNTPase activity and decreased ability to restrict infection by viruses. 7 Publications1
Mutagenesisi593P → A: Promotes ability to restrict infection by viruses. 1 Publication1
Mutagenesisi609R → A or E: Abolishes proteasomal degradation triggered by the viral accessory protein vpx. 1 Publication1
Mutagenesisi617R → A or E: Abolishes proteasomal degradation triggered by the viral accessory protein vpx. 1 Publication1
Mutagenesisi622K → A or E: Abolishes proteasomal degradation triggered by the viral accessory protein vpx. 1 Publication1

Keywords - Diseasei

Aicardi-Goutieres syndrome, Disease mutation

Organism-specific databases

DisGeNETi25939
GeneReviewsiSAMHD1
MalaCardsiSAMHD1
MIMi612952 phenotype
614415 phenotype
OpenTargetsiENSG00000101347
Orphaneti51 Aicardi-Goutieres syndrome
481662 Familial Chilblain lupus
PharmGKBiPA34938

Polymorphism and mutation databases

BioMutaiSAMHD1
DMDMi22257047

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001537321 – 626Deoxynucleoside triphosphate triphosphohydrolase SAMHD1Add BLAST626

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1 Publication1
Modified residuei18PhosphoserineBy similarity1
Modified residuei21PhosphothreonineBy similarity1
Modified residuei25PhosphothreonineBy similarity1
Modified residuei33PhosphoserineCombined sources1
Modified residuei93PhosphoserineCombined sources1
Cross-linki467Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Cross-linki469Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Cross-linki492Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei592Phosphothreonine; by CDK1Combined sources6 Publications1
Cross-linki622Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Post-translational modificationi

Phosphorylation at Thr-592 by CDK1 acts as a switch to control deoxynucleoside triphosphate (dNTPase)-dependent and -independent functions (PubMed:29670289). Phosphorylation at Thr-592 takes place in cycling cells: it reduces the stability of the homotetramer, impairing the dNTPase activity and subsequent ability to restrict infection by viruses (PubMed:23602554, PubMed:23601106, PubMed:26294762, PubMed:26431200). It also inhibits ability to suppress LINE-1 retrotransposon activity (PubMed:29610582). In contrast, phosphorylation at Thr-592 promotes DNA end resection at stalled replication forks in response to DNA damage (PubMed:29670289).6 Publications
(Microbial infection) Ubiquitinated following interaction with HIV-2 viral protein Vpx; Vpx promotes interaction and with a DCX (DDB1-CUL4-X-box) E3 ubiquitin ligase, leading to proteasomal degradation.4 Publications

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9Y3Z3
PaxDbiQ9Y3Z3
PeptideAtlasiQ9Y3Z3
PRIDEiQ9Y3Z3
ProteomicsDBi86088

PTM databases

CarbonylDBiQ9Y3Z3
iPTMnetiQ9Y3Z3
PhosphoSitePlusiQ9Y3Z3

Expressioni

Tissue specificityi

Expressed in heart, skeletal muscle, spleen, liver, small intestine, placenta, lung and peripheral blood leukocytes (PubMed:11064105). No expression is seen in brain and thymus (PubMed:11064105).1 Publication

Inductioni

By IFNG/IFN-gamma. Up-regulated in TNF treated lung fibroblasts.2 Publications

Gene expression databases

BgeeiENSG00000101347 Expressed in 234 organ(s), highest expression level in bronchial epithelial cell
CleanExiHS_SAMHD1
GenevisibleiQ9Y3Z3 HS

Organism-specific databases

HPAiHPA047072

Interactioni

Subunit structurei

Homodimer; in absence of GTP and dNTP (PubMed:24141705, PubMed:24217394, PubMed:28229507, PubMed:25760601). Homotetramer; in GTP- and dNTP-bound form (PubMed:23601106, PubMed:26101257, PubMed:24141705, PubMed:24217394, PubMed:28229507, PubMed:26294762, PubMed:26431200, PubMed:25288794, PubMed:25267621, PubMed:25760601). Interacts with MRE11; leading to stimulate the exonuclease activity of MRE11 (PubMed:28834754, PubMed:29670289). Interacts with RBBP8/CtIP (PubMed:28834754).12 Publications
(Microbial infection) Interacts with HIV-2 viral protein Vpx; promoting interaction with a E3 ubiquitin-protein ligase complex containing DCAF1, leading to subsequent ubiquitination and degradation of SAMHD1.3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi117436, 75 interactors
DIPiDIP-50704N
IntActiQ9Y3Z3, 30 interactors
STRINGi9606.ENSP00000262878

Structurei

Secondary structure

1626
Legend: HelixTurnBeta strandPDB Structure known for this area
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