TCPC_ECOL6
ID TCPC_ECOL6 Reviewed; 307 AA.
AC A0A0H2V8B5;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-SEP-2015, sequence version 1.
DT 03-AUG-2022, entry version 21.
DE RecName: Full=NAD(+) hydrolase TcpC {ECO:0000305};
DE EC=3.2.2.6 {ECO:0000269|PubMed:29395922};
DE AltName: Full=NADP(+) hydrolase TcpC {ECO:0000305};
DE EC=3.2.2.- {ECO:0000269|PubMed:29395922};
DE AltName: Full=TIR domain-containing protein in E.coli {ECO:0000303|PubMed:18327267};
DE Short=tcpC {ECO:0000303|PubMed:18327267};
GN Name=TcpC {ECO:0000303|PubMed:18327267};
GN OrderedLocusNames=c2398 {ECO:0000312|EMBL:AAN80857.1};
OS Escherichia coli O6:H1 (strain CFT073 / ATCC 700928 / UPEC).
OC Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales;
OC Enterobacteriaceae; Escherichia.
OX NCBI_TaxID=199310;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=CFT073 / ATCC 700928 / UPEC;
RX PubMed=12471157; DOI=10.1073/pnas.252529799;
RA Welch R.A., Burland V., Plunkett G. III, Redford P., Roesch P., Rasko D.,
RA Buckles E.L., Liou S.-R., Boutin A., Hackett J., Stroud D., Mayhew G.F.,
RA Rose D.J., Zhou S., Schwartz D.C., Perna N.T., Mobley H.L.T.,
RA Donnenberg M.S., Blattner F.R.;
RT "Extensive mosaic structure revealed by the complete genome sequence of
RT uropathogenic Escherichia coli.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:17020-17024(2002).
RN [2]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH HOST MYD88.
RX PubMed=18327267; DOI=10.1038/nm1734;
RA Cirl C., Wieser A., Yadav M., Duerr S., Schubert S., Fischer H.,
RA Stappert D., Wantia N., Rodriguez N., Wagner H., Svanborg C., Miethke T.;
RT "Subversion of Toll-like receptor signaling by a unique family of bacterial
RT Toll/interleukin-1 receptor domain-containing proteins.";
RL Nat. Med. 14:399-406(2008).
RN [3]
RP FUNCTION.
RX PubMed=20886104; DOI=10.1371/journal.ppat.1001120;
RA Yadav M., Zhang J., Fischer H., Huang W., Lutay N., Cirl C., Lum J.,
RA Miethke T., Svanborg C.;
RT "Inhibition of TIR domain signaling by TcpC: MyD88-dependent and
RT independent effects on Escherichia coli virulence.";
RL PLoS Pathog. 6:E1001120-E1001120(2010).
RN [4]
RP INTERACTION WITH HOST MYD88 AND TLR4, AND MUTAGENESIS OF 272-VAL--TYR-275.
RX PubMed=23569230; DOI=10.1073/pnas.1215770110;
RA Snyder G.A., Cirl C., Jiang J., Chen K., Waldhuber A., Smith P.,
RA Roemmler F., Snyder N., Fresquez T., Duerr S., Tjandra N., Miethke T.,
RA Xiao T.S.;
RT "Molecular mechanisms for the subversion of MyD88 signaling by TcpC from
RT virulent uropathogenic Escherichia coli.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:6985-6990(2013).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF
RP GLU-244, AND ACTIVE SITE.
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
CC (TLR)-mediated cytokine production upon infection, thereby increasing
CC bacterial burden in the urinary tract and promoting renal tissue damage
CC (PubMed:18327267, PubMed:20886104). Acts as a NAD(+) hydrolase (NADase)
CC by catalyzing cleavage of NAD(+) into ADP-D-ribose (ADPR) and
CC nicotinamide (PubMed:29395922). Also able to hydrolyze NADP(+), but not
CC other NAD(+)-related molecules (PubMed:29395922).
CC {ECO:0000269|PubMed:18327267, ECO:0000269|PubMed:20886104,
CC 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=196 uM for NAD(+) {ECO:0000269|PubMed:29395922};
CC -!- SUBUNIT: Interacts with host MYD88 (PubMed:18327267, PubMed:23569230).
CC Interacts with host TLR4 (PubMed:23569230).
CC {ECO:0000269|PubMed:18327267, ECO:0000269|PubMed:23569230}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18327267}. Membrane
CC {ECO:0000255}; Single-pass membrane protein {ECO:0000255}.
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; AE014075; AAN80857.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A0H2V8B5; -.
DR SMR; A0A0H2V8B5; -.
DR STRING; 199310.c2398; -.
DR EnsemblBacteria; AAN80857; AAN80857; c2398.
DR KEGG; ecc:c2398; -.
DR eggNOG; COG4916; Bacteria.
DR HOGENOM; CLU_078739_0_0_6; -.
DR Proteomes; UP000001410; Chromosome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0034125; P:negative regulation of MyD88-dependent toll-like receptor signaling pathway; 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 Hydrolase; Membrane; NAD; Secreted; Transmembrane; Transmembrane helix;
KW Virulence.
FT CHAIN 1..307
FT /note="NAD(+) hydrolase TcpC"
FT /id="PRO_0000449143"
FT TRANSMEM 22..42
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 169..303
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT ACT_SITE 244
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204,
FT ECO:0000305|PubMed:29395922"
FT BINDING 178..179
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT BINDING 208
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT MUTAGEN 244
FT /note="E->A: Loss of NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:29395922"
FT MUTAGEN 272..275
FT /note="Missing: Decreased ability to suppress TLR-mediated
FT cytokine production in host."
FT /evidence="ECO:0000269|PubMed:23569230"
SQ SEQUENCE 307 AA; 36426 MW; 0572F0AB92B7C5ED CRC64;
MIAYENIEFF ICLVNVLGNN MYNILFFIFL SIAIPFLLFL AWKQHLKTKE IRSYLLKEGY
NIIFNGEGNS YLAFNISNAT FRAGNLTSND YFQASISYIH DYRWEWKEVE AKKINNIFII
YISNIDFPSQ KLFYRNNKSL AEIDWAKLQA IFHQPYEIQN DVMQDNNNTH YDFFISHAKE
DKDTFVRPLV DELNRLGVII WYDEQTLEVG DSLRRNIDLG LRKANYGIVI LSHNFLNKKW
TQYELDSLIN RAVYDDNKII LPIWHNINAQ EVSKYSHYLA DKMALQTSLY SVKEIARELA
EIAYRRR
