TIRS_STAAS
ID TIRS_STAAS Reviewed; 280 AA.
AC P0DTS9;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 26-FEB-2020, sequence version 1.
DT 03-AUG-2022, entry version 7.
DE RecName: Full=NAD(+) hydrolase TirS {ECO:0000305};
DE EC=3.2.2.6 {ECO:0000269|PubMed:29395922};
DE AltName: Full=NADP(+) hydrolase TirS {ECO:0000305};
DE EC=3.2.2.- {ECO:0000269|PubMed:29395922};
DE AltName: Full=TIR domain-containing protein in S.aureus {ECO:0000303|PubMed:24481289};
GN Name=tirS {ECO:0000303|PubMed:24481289}; OrderedLocusNames=SAS0038;
OS Staphylococcus aureus (strain MSSA476).
OC Bacteria; Firmicutes; Bacilli; Bacillales; Staphylococcaceae;
OC Staphylococcus.
OX NCBI_TaxID=282459;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=MSSA476;
RX PubMed=15213324; DOI=10.1073/pnas.0402521101;
RA Holden M.T.G., Feil E.J., Lindsay J.A., Peacock S.J., Day N.P.J.,
RA Enright M.C., Foster T.J., Moore C.E., Hurst L., Atkin R., Barron A.,
RA Bason N., Bentley S.D., Chillingworth C., Chillingworth T., Churcher C.,
RA Clark L., Corton C., Cronin A., Doggett J., Dowd L., Feltwell T., Hance Z.,
RA Harris B., Hauser H., Holroyd S., Jagels K., James K.D., Lennard N.,
RA Line A., Mayes R., Moule S., Mungall K., Ormond D., Quail M.A.,
RA Rabbinowitsch E., Rutherford K.M., Sanders M., Sharp S., Simmonds M.,
RA Stevens K., Whitehead S., Barrell B.G., Spratt B.G., Parkhill J.;
RT "Complete genomes of two clinical Staphylococcus aureus strains: evidence
RT for the rapid evolution of virulence and drug resistance.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:9786-9791(2004).
RN [2]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24481289; DOI=10.1159/000357618;
RA Askarian F., van Sorge N.M., Sangvik M., Beasley F.C., Henriksen J.R.,
RA Sollid J.U., van Strijp J.A., Nizet V., Johannessen M.;
RT "A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-
RT mediated NF-kappaB signaling.";
RL J. Innate Immun. 6:485-498(2014).
RN [3]
RP FUNCTION.
RX PubMed=28060920; DOI=10.1371/journal.ppat.1006092;
RA Patot S., Imbert P.R., Baude J., Martins Simoes P., Campergue J.B.,
RA Louche A., Nijland R., Bes M., Tristan A., Laurent F., Fischer A.,
RA Schrenzel J., Vandenesch F., Salcedo S.P., Francois P., Lina G.;
RT "The TIR homologue lies near resistance genes in Staphylococcus aureus,
RT coupling modulation of virulence and antimicrobial susceptibility.";
RL PLoS Pathog. 13:E1006092-E1006092(2017).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF GLU-216.
RX PubMed=29395922; DOI=10.1016/j.cub.2017.12.024;
RA Essuman K., Summers D.W., Sasaki Y., Mao X., Yim A.K.Y., DiAntonio A.,
RA Milbrandt J.;
RT "TIR domain proteins are an ancient family of NAD+-consuming enzymes.";
RL Curr. Biol. 28:421-430(2018).
CC -!- FUNCTION: Virulence factor that suppresses host Toll-like receptor 2
CC (TLR2)-mediated NF-kappa-B signaling upon infection (PubMed:24481289,
CC PubMed:28060920). NAD(+) hydrolase (NADase) that catalyzes cleavage of
CC NAD(+) into ADP-D-ribose (ADPR) and nicotinamide (PubMed:29395922).
CC Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules
CC (PubMed:29395922). Able to reduce NAD(+) levels in host cells
CC (PubMed:29395922). {ECO:0000269|PubMed:24481289,
CC ECO:0000269|PubMed:28060920, ECO:0000269|PubMed:29395922}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide;
CC Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6;
CC Evidence={ECO:0000269|PubMed:29395922};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302;
CC Evidence={ECO:0000269|PubMed:29395922};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + NADP(+) = ADP-D-ribose 2'-phosphate + H(+) +
CC nicotinamide; Xref=Rhea:RHEA:19849, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:58673; Evidence={ECO:0000269|PubMed:29395922};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19850;
CC Evidence={ECO:0000269|PubMed:29395922};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=490 uM for NAD(+) {ECO:0000269|PubMed:29395922};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:24481289}.
CC -!- DOMAIN: The TIR domain mediates NAD(+) hydrolase (NADase) activity.
CC Self-association of TIR domains is required for NADase activity.
CC {ECO:0000255|PROSITE-ProRule:PRU00204}.
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DR EMBL; BX571857; CAG41810.1; -; Genomic_DNA.
DR RefSeq; WP_000114516.1; NC_002953.3.
DR AlphaFoldDB; P0DTS9; -.
DR SMR; P0DTS9; -.
DR KEGG; sas:SAS0038; -.
DR OMA; FISHAWE; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0050135; F:NAD(P)+ nucleosidase activity; IDA:UniProtKB.
DR GO; GO:0003953; F:NAD+ nucleosidase activity; IDA:UniProtKB.
DR GO; GO:0061809; F:NAD+ nucleotidase, cyclic ADP-ribose generating; IEA:UniProtKB-EC.
DR GO; GO:0019677; P:NAD catabolic process; IDA:UniProtKB.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
DR Gene3D; 3.40.50.10140; -; 1.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR Pfam; PF13676; TIR_2; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF52200; SSF52200; 1.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW Coiled coil; Hydrolase; NAD; Secreted; Virulence.
FT CHAIN 1..280
FT /note="NAD(+) hydrolase TirS"
FT /id="PRO_0000449146"
FT DOMAIN 141..275
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT COILED 22..94
FT /evidence="ECO:0000255"
FT ACT_SITE 216
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204,
FT ECO:0000305|PubMed:29395922"
FT BINDING 150..151
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT BINDING 180
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT MUTAGEN 216
FT /note="E->A: Loss of NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:29395922"
SQ SEQUENCE 280 AA; 32811 MW; AF8B2752C7CC67E1 CRC64;
MSVLETKLKS QMSKSAKIAR NMNKLPDEID RLRKRIERIN KKRKPTSSNI RDLEKSNKQL
VTKQQKLADL QVEYTKIEKK INETKINLQK EQSRNQKKLS SMLDKNTKGN EEIMEKLLTN
SDQINEISNQ IKKAVNQKEI IEYDVFLSHS SLDKEDYVSK ISEKLIEKGL KVFEDVKVFE
IGKSQTETMN MGILNSRFVV VFLSPNFIES GWSRYEFLSF LNREINEEHV IILPIWHKVS
VEDVRAYNPY LVDKYALNTS DFSIEEIVEK IYQVIVNSKN
