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Protein

Deoxynucleoside triphosphate triphosphohydrolase SAMHD1

Gene

Samhd1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Isoform 1: 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 (By similarity). Has deoxynucleoside triphosphate (dNTPase) activity, which is required to restrict infection by viruses: 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:23972988, PubMed:23872947, PubMed:26667483, PubMed:29379009). Likewise, suppresses LINE-1 retrotransposon activity (PubMed:26667483). In addition to virus restriction, dNTPase activity acts as a regulator of DNA precursor pools by regulating dNTP pools (By similarity). Phosphorylation at Thr-634 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 (By similarity). 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 (By similarity). 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 (By similarity). Ability to promote DNA end resection at stalled replication forks is independent of dNTPase activity (By similarity). Enhances immunoglobulin hypermutation in B-lymphocytes by promoting transversion mutation (PubMed:29669924).By similarity5 Publications

Catalytic activityi

dNTP + H2O = Deoxynucleoside + triphosphate.1 Publication

Cofactori

Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

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. Allosteric activation promotes the formation of highly active homotetramers. Isoform 1: Phosphorylation at Thr-634 impairs homotetramerization, thereby inhibiting dNTPase activity, leading to reduced ability to restrict infection by viruses.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei148GTPCombined sources1 Publication1
Binding sitei151dNTP; via amide nitrogen; shared with neighboring subunitBy similarity1
Binding sitei181SubstrateBy similarity1
Binding sitei196SubstrateBy similarity1
Metal bindingi199Zinc; via tele nitrogenCombined sources1 Publication1
Metal bindingi238Zinc; via tele nitrogenCombined sources1 Publication1
Metal bindingi239ZincCombined sources1 Publication1
Binding sitei242SubstrateBy similarity1
Active sitei265By similarity1
Metal bindingi343ZincCombined sources1 Publication1
Binding sitei347SubstrateBy similarity1
Binding sitei351SubstrateBy similarity1
Binding sitei365dNTPBy similarity1
Binding sitei401dNTPBy similarity1
Binding sitei409SubstrateBy similarity1
Binding sitei419dNTP; shared with neighboring subunitBy similarity1
Binding sitei420dNTP; shared with neighboring subunitCombined sources1 Publication1
Binding sitei494GTP; shared with neighboring subunitCombined sources1 Publication1
Binding sitei498GTP; shared with neighboring subunitBy similarity1
Binding sitei565dNTPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi169 – 177GTPCombined sources1 Publication9
Nucleotide bindingi395 – 397dNTPBy similarity3

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-MMU-8956319 Nucleobase catabolism

Names & Taxonomyi

Protein namesi
Recommended name:
Deoxynucleoside triphosphate triphosphohydrolase SAMHD1Curated (EC:3.1.5.-1 Publication)
Short name:
dNTPaseCurated
Alternative name(s):
Interferon-gamma-inducible protein Mg111 Publication
SAM domain and HD domain-containing protein 1Curated
Short name:
mSAMHD11 Publication
Gene namesi
Name:Samhd1Imported
Synonyms:Mg111 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:1927468 Samhd1

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

Disruption phenotypei

Mice are viable and fertile but show increased cellular dNTP concentrations and impaired ability to restrict retroviral replication in lymphocytes, macrophages and dendritic cells (PubMed:23972988). Mice also diplay interferon (IFN)-beta-dependent transcriptional up-regulation of type I IFN-inducible genes in various cell types indicative of spontaneous IFN production (PubMed:23972988, PubMed:23872947).2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi109F → L in LCH mutant; abolishes formation of the tetramer and deoxynucleoside triphosphate (dNTPase) activity; when associated with C-112 and H-143. 1 Publication1
Mutagenesisi112F → C in LCH mutant; abolishes formation of the tetramer and deoxynucleoside triphosphate (dNTPase) activity; when associated with L-109 and H-143. 1 Publication1
Mutagenesisi143R → H in LCH mutant; abolishes formation of the tetramer and deoxynucleoside triphosphate (dNTPase) activity; when associated with L-109 and C-112. 1 Publication1
Mutagenesisi634T → A or V: Increased ability to restrict LINE-1 retrotransposon activity. 1 Publication1
Mutagenesisi634T → E: Mimicks phosphorylation state, reduced ability to restrict LINE-1 retrotransposon activity. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001537331 – 658Deoxynucleoside triphosphate triphosphohydrolase SAMHD1Add BLAST658

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei49PhosphoserineCombined sources1
Modified residuei52PhosphothreonineCombined sources1
Modified residuei55PhosphoserineCombined sources1
Modified residuei56PhosphothreonineCombined sources1
Modified residuei64PhosphoserineBy similarity1
Modified residuei125PhosphoserineBy similarity1
Cross-linki509Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)By similarity
Modified residuei634PhosphothreonineCombined sources1 Publication1

Post-translational modificationi

Isoform 1: Phosphorylation at Thr-634 by CDK1 acts as a switch to control deoxynucleoside triphosphate (dNTPase)-dependent and -independent functions (PubMed:26667483) (By similarity). Phosphorylation at Thr-634 takes place in cycling cells: it reduces the stability of the homotetramer, impairing the dNTPase activity and subsequent ability to restrict infection by viruses (Probable). It also inhibits ability to suppress LINE-1 retrotransposon activity (PubMed:26667483). In contrast, phosphorylation at Thr-634 promotes DNA end resection at stalled replication forks in response to DNA damage (By similarity).By similarity1 Publication1 Publication
Isoform 2: Not phosphorylated by CDK1 at the C-terminus.Curated

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ60710
MaxQBiQ60710
PaxDbiQ60710
PeptideAtlasiQ60710
PRIDEiQ60710

PTM databases

CarbonylDBiQ60710
iPTMnetiQ60710
PhosphoSitePlusiQ60710
SwissPalmiQ60710

Miscellaneous databases

PMAP-CutDBiQ60710

Expressioni

Inductioni

Gene expression databases

BgeeiENSMUSG00000027639 Expressed in 267 organ(s), highest expression level in decidua
CleanExiMM_SAMHD1

Interactioni

Subunit structurei

Homodimer; in absence of GTP and dNTP (By similarity). Homotetramer; in GTP- and dNTP-bound form (PubMed:29379009). Interacts with MRE11; leading to stimulate the exonuclease activity of MRE11 (By similarity). Interacts with RBBP8/CtIP (By similarity).By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi207791, 11 interactors
IntActiQ60710, 3 interactors
MINTiQ60710
STRINGi10090.ENSMUSP00000059717

Structurei

Secondary structure

1658
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ60710
SMRiQ60710
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini77 – 142SAMPROSITE-ProRule annotationAdd BLAST66
Domaini196 – 348HDPROSITE-ProRule annotationAdd BLAST153

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni341 – 347Substrate bindingBy similarity7
Regioni413 – 418Substrate bindingBy similarity6

Domaini

In mouse, the SAM domain is required for deoxynucleoside triphosphate (dNTPase) activity and ability to restrict infection by viruses. It acts by capping allosteric sites.1 Publication

Sequence similaritiesi

Belongs to the SAMHD1 family.Curated

Phylogenomic databases

eggNOGiKOG2681 Eukaryota
COG1078 LUCA
GeneTreeiENSGT00390000013867
HOGENOMiHOG000264286
HOVERGENiHBG054208
InParanoidiQ60710
KOiK22544
OrthoDBiEOG091G060J
PhylomeDBiQ60710
TreeFamiTF316113

Family and domain databases

CDDicd00077 HDc, 1 hit
InterProiView protein in InterPro
IPR003607 HD/PDEase_dom
IPR006674 HD_domain
IPR001660 SAM
IPR013761 SAM/pointed_sf
PfamiView protein in Pfam
PF01966 HD, 1 hit
PF07647 SAM_2, 1 hit
SMARTiView protein in SMART
SM00471 HDc, 1 hit
SM00454 SAM, 1 hit
SUPFAMiSSF47769 SSF47769, 1 hit
PROSITEiView protein in PROSITE
PS51831 HD, 1 hit
PS50105 SAM_DOMAIN, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q60710-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MDSLLGCGVS AAAREPVPRY LTSQPRVSEV AMQSAPLEQP AKRPRCDGSP
60 70 80 90 100
RTPPSTPPAT ANLSADDDFQ NTDLRTWEPE DVCSFLENRG FREKKVLDIF
110 120 130 140 150
RDNKIAGSFL PFLDEDRLED LGVSSLEERK KMIECIQQLS QSRIDLMKVF
160 170 180 190 200
NDPIHGHIEF HPLLIRIIDT PQFQRLRYIK QLGGGYYVFP GASHNRFEHS
210 220 230 240 250
LGVGYLAGCL VRALAEKQPE LQISERDILC VQIAGLCHDL GHGPFSHMFD
260 270 280 290 300
GRFIPRARPE KKWKHEQGSI EMFEHLVNSN ELKLVMKNYG LVPEEDITFI
310 320 330 340 350
KEQIMGPPIT PVKDSLWPYK GRPATKSFLY EIVSNKRNGI DVDKWDYFAR
360 370 380 390 400
DCHHLGIQNN FDYKRFIKFA RICEVEYKVK EDKTYIRKVK HICSREKEVG
410 420 430 440 450
NLYDMFHTRN CLHRRAYQHK ISNLIDIMIT DAFLKADPYV EITGTAGKKF
460 470 480 490 500
RISTAIDDME AFTKLTDNIF LEVLHSTDPQ LSEAQSILRN IECRNLYKYL
510 520 530 540 550
GETQPKREKI RKEEYERLPQ EVAKAKPEKA PDVELKAEDF IVDVINVDYG
560 570 580 590 600
MEDKNPIDRV HFYCKSNSKQ AVRINKEQVS QLLPEKFAEQ LIRVYCKKKD
610 620 630 640 650
GKSLDAAGKH FVQWCALRDF TKPQDGDIIA PLITPLKWNN KTSSCLQEVS

KVKTCLKF
Length:658
Mass (Da):75,893
Last modified:July 18, 2018 - v3
Checksum:i8ED07CE9EB6239D6
GO
Isoform 2 (identifier: Q60710-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     625-658: DGDIIAPLITPLKWNNKTSSCLQEVSKVKTCLKF → QCGAGEMAEDPDSIPSTQQPHAAHNQL

Show »
Length:651
Mass (Da):74,935
Checksum:i691307229BD269DA
GO

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9PYG9E9PYG9_MOUSE
Deoxynucleoside triphosphate tripho...
Samhd1
582Annotation score:
E0CXZ5E0CXZ5_MOUSE
Deoxynucleoside triphosphate tripho...
Samhd1
150Annotation score:
F6TVP2F6TVP2_MOUSE
Deoxynucleoside triphosphate tripho...
Samhd1
631Annotation score:

Sequence cautioni

The sequence AAA66219 differs from that shown. Reason: Frameshift at position 607.Curated
The sequence AAA66219 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence AAH12721 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence AAH67198 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAC35801 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAE30313 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAE31954 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti371R → L in BAE31954 (PubMed:16141072).Curated1
Sequence conflicti371R → L in BAE30313 (PubMed:16141072).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_059661625 – 658DGDII…TCLKF → QCGAGEMAEDPDSIPSTQQP HAAHNQL in isoform 2. Add BLAST34

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U15635 mRNA Translation: AAA66219.1 Sequence problems.
AK054490 mRNA Translation: BAC35801.1 Different initiation.
AK151335 mRNA Translation: BAE30313.1 Different initiation.
AK153390 mRNA Translation: BAE31954.1 Different initiation.
AL669828 Genomic DNA No translation available.
BC012721 mRNA Translation: AAH12721.1 Different initiation.
BC067198 mRNA Translation: AAH67198.1 Different initiation.
CCDSiCCDS16973.2 [Q60710-1]
CCDS50783.1 [Q60710-2]
PIRiI49127
RefSeqiNP_001132992.1, NM_001139520.1 [Q60710-2]
NP_061339.3, NM_018851.3 [Q60710-1]
UniGeneiMm.248478
Mm.468781

Genome annotation databases

EnsembliENSMUST00000057725; ENSMUSP00000059717; ENSMUSG00000027639 [Q60710-1]
ENSMUST00000088523; ENSMUSP00000085880; ENSMUSG00000027639 [Q60710-2]
GeneIDi56045
KEGGimmu:56045

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U15635 mRNA Translation: AAA66219.1 Sequence problems.
AK054490 mRNA Translation: BAC35801.1 Different initiation.
AK151335 mRNA Translation: BAE30313.1 Different initiation.
AK153390 mRNA Translation: BAE31954.1 Different initiation.
AL669828 Genomic DNA No translation available.
BC012721 mRNA Translation: AAH12721.1 Different initiation.
BC067198 mRNA Translation: AAH67198.1 Different initiation.
CCDSiCCDS16973.2 [Q60710-1]
CCDS50783.1 [Q60710-2]
PIRiI49127
RefSeqiNP_001132992.1, NM_001139520.1 [Q60710-2]
NP_061339.3, NM_018851.3 [Q60710-1]
UniGeneiMm.248478
Mm.468781

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
6BRGX-ray3.50A/B/C/D1-658[»]
6BRHX-ray3.40A/B1-658[»]
6BRKX-ray3.50A1-658[»]
ProteinModelPortaliQ60710
SMRiQ60710
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi207791, 11 interactors
IntActiQ60710, 3 interactors
MINTiQ60710
STRINGi10090.ENSMUSP00000059717

PTM databases

CarbonylDBiQ60710
iPTMnetiQ60710
PhosphoSitePlusiQ60710
SwissPalmiQ60710

Proteomic databases

EPDiQ60710
MaxQBiQ60710
PaxDbiQ60710
PeptideAtlasiQ60710
PRIDEiQ60710

Protocols and materials databases

DNASUi56045
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000057725; ENSMUSP00000059717; ENSMUSG00000027639 [Q60710-1]
ENSMUST00000088523; ENSMUSP00000085880; ENSMUSG00000027639 [Q60710-2]
GeneIDi56045
KEGGimmu:56045

Organism-specific databases

CTDi25939
MGIiMGI:1927468 Samhd1

Phylogenomic databases

eggNOGiKOG2681 Eukaryota
COG1078 LUCA
GeneTreeiENSGT00390000013867
HOGENOMiHOG000264286
HOVERGENiHBG054208
InParanoidiQ60710
KOiK22544
OrthoDBiEOG091G060J
PhylomeDBiQ60710
TreeFamiTF316113

Enzyme and pathway databases

ReactomeiR-MMU-8956319 Nucleobase catabolism

Miscellaneous databases

ChiTaRSiSamhd1 mouse
PMAP-CutDBiQ60710
PROiPR:Q60710
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000027639 Expressed in 267 organ(s), highest expression level in decidua
CleanExiMM_SAMHD1

Family and domain databases

CDDicd00077 HDc, 1 hit
InterProiView protein in InterPro
IPR003607 HD/PDEase_dom
IPR006674 HD_domain
IPR001660 SAM
IPR013761 SAM/pointed_sf
PfamiView protein in Pfam
PF01966 HD, 1 hit
PF07647 SAM_2, 1 hit
SMARTiView protein in SMART
SM00471 HDc, 1 hit
SM00454 SAM, 1 hit
SUPFAMiSSF47769 SSF47769, 1 hit
PROSITEiView protein in PROSITE
PS51831 HD, 1 hit
PS50105 SAM_DOMAIN, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiSAMH1_MOUSE
AccessioniPrimary (citable) accession number: Q60710
Secondary accession number(s): E9Q0K6
, F8WJE0, Q3U5X2, Q543A4, Q91VK8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: July 18, 2018
Last modified: November 7, 2018
This is version 153 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, 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
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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