PTKA_MYCTU
ID PTKA_MYCTU Reviewed; 291 AA.
AC P9WPI9; L0TBP3; P68911; Q10515; Q10516;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 46.
DE RecName: Full=Tyrosine-protein kinase PtkA {ECO:0000305};
DE EC=2.7.10.- {ECO:0000269|PubMed:19366344, ECO:0000269|PubMed:22888002, ECO:0000269|PubMed:25535696, ECO:0000269|PubMed:29317718, ECO:0000269|PubMed:29724125};
DE AltName: Full=Protein tyrosine kinase A {ECO:0000303|PubMed:19366344};
GN Name=ptkA {ECO:0000303|PubMed:19366344}; OrderedLocusNames=Rv2232;
GN ORFNames=MTCY427.13/MTCY427.14;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP SEQUENCE REVISION.
RX PubMed=12368430; DOI=10.1099/00221287-148-10-2967;
RA Camus J.-C., Pryor M.J., Medigue C., Cole S.T.;
RT "Re-annotation of the genome sequence of Mycobacterium tuberculosis
RT H37Rv.";
RL Microbiology 148:2967-2973(2002).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION
RP WITH PTPA, PHOSPHORYLATION AT TYR-262, AND MUTAGENESIS OF ASP-85; TYR-146;
RP TYR-150; LYS-184; LYS-217; TYR-262 AND LYS-270.
RC STRAIN=H37Rv;
RX PubMed=19366344; DOI=10.1042/bj20090478;
RA Bach H., Wong D., Av-Gay Y.;
RT "Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose
RT substrate is PtpA.";
RL Biochem. J. 420:155-160(2009).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH PTPA, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=22888002; DOI=10.1074/jbc.m112.399261;
RA Stehle T., Sreeramulu S., Lohr F., Richter C., Saxena K., Jonker H.R.,
RA Schwalbe H.;
RT "The apo-structure of the low molecular weight protein-tyrosine phosphatase
RT A (MptpA) from Mycobacterium tuberculosis allows for better target-specific
RT drug development.";
RL J. Biol. Chem. 287:34569-34582(2012).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF TYR-262.
RX PubMed=25535696; DOI=10.1016/j.febslet.2014.12.015;
RA Zhou P., Li W., Wong D., Xie J., Av-Gay Y.;
RT "Phosphorylation control of protein tyrosine phosphatase A activity in
RT Mycobacterium tuberculosis.";
RL FEBS Lett. 589:326-331(2015).
RN [7]
RP ACTIVITY REGULATION, PHOSPHORYLATION BY ESTPKS, AND INTERACTION WITH
RP ESTPKS.
RX PubMed=26417687; DOI=10.1016/j.bbrc.2015.09.124;
RA Zhou P., Wong D., Li W., Xie J., Av-Gay Y.;
RT "Phosphorylation of Mycobacterium tuberculosis protein tyrosine kinase A
RT PtkA by Ser/Thr protein kinases.";
RL Biochem. Biophys. Res. Commun. 467:421-426(2015).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH TRXB, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=29317718; DOI=10.1038/s41598-017-18547-9;
RA Wong D., Li W., Chao J.D., Zhou P., Narula G., Tsui C., Ko M., Xie J.,
RA Martinez-Frailes C., Av-Gay Y.;
RT "Protein tyrosine kinase, PtkA, is required for Mycobacterium tuberculosis
RT growth in macrophages.";
RL Sci. Rep. 8:155-155(2018).
RN [9]
RP PHOSPHORYLATION, ACTIVITY REGULATION, AND DOMAIN.
RX PubMed=29494752; DOI=10.1002/1873-3468.13022;
RA Niesteruk A., Hutchison M., Sreeramulu S., Jonker H.R.A., Richter C.,
RA Abele R., Bock C., Schwalbe H.;
RT "Structural characterization of the intrinsically disordered domain of
RT Mycobacterium tuberculosis protein tyrosine kinase A.";
RL FEBS Lett. 592:1233-1245(2018).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH PTPA, AND BIOTECHNOLOGY.
RX PubMed=29724125; DOI=10.1080/1061186x.2018.1473407;
RA Jaiswal S., Chatterjee A., Pandey S., Lata K., Gadi R.K., Manda R.,
RA Kumar S., Reddy M.S., Ramachandran R., Srivastava K.K.;
RT "Mycobacterial protein tyrosine kinase, PtkA phosphorylates PtpA at
RT tyrosine residues and the mechanism is stalled by the novel series of
RT inhibitors.";
RL J. Drug. Target. 27:51-59(2019).
RN [11]
RP DOMAIN.
RX PubMed=32157138; DOI=10.1038/s41598-020-61132-w;
RA Nagpal P., Jamal S., Singh H., Ali W., Tanweer S., Sharma R., Grover A.,
RA Grover S.;
RT "Long-range replica exchange molecular dynamics guided drug repurposing
RT against tyrosine kinase PtkA of Mycobacterium tuberculosis.";
RL Sci. Rep. 10:4413-4413(2020).
RN [12] {ECO:0007744|PDB:6F2X}
RP STRUCTURE BY NMR OF 76-291, PHOSPHORYLATION AT TYR-262, ACTIVITY
RP REGULATION, AND DOMAIN.
RX PubMed=29884774; DOI=10.1074/jbc.ra117.000120;
RA Niesteruk A., Jonker H.R.A., Richter C., Linhard V., Sreeramulu S.,
RA Schwalbe H.;
RT "The domain architecture of PtkA, the first tyrosine kinase from
RT Mycobacterium tuberculosis, differs from the conventional kinase
RT architecture.";
RL J. Biol. Chem. 293:11823-11836(2018).
CC -!- FUNCTION: Required for growth within macrophages (PubMed:29317718).
CC Catalyzes the phosphorylation of PtpA on the tyrosine residues at
CC positions 128 and 129, thereby increasing PtpA phosphatase activity and
CC promoting pathogenicity (PubMed:19366344, PubMed:22888002,
CC PubMed:25535696, PubMed:29724125). Also phosphorylates the thioredoxin
CC reductase TrxB (PubMed:29317718). {ECO:0000269|PubMed:19366344,
CC ECO:0000269|PubMed:22888002, ECO:0000269|PubMed:25535696,
CC ECO:0000269|PubMed:29317718, ECO:0000269|PubMed:29724125}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:19366344, ECO:0000269|PubMed:22888002,
CC ECO:0000269|PubMed:25535696, ECO:0000269|PubMed:29317718,
CC ECO:0000269|PubMed:29724125};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10597;
CC Evidence={ECO:0000269|PubMed:19366344, ECO:0000269|PubMed:22888002,
CC ECO:0000269|PubMed:25535696, ECO:0000269|PubMed:29317718,
CC ECO:0000269|PubMed:29724125};
CC -!- ACTIVITY REGULATION: Activity is increased by phosphorylation.
CC {ECO:0000269|PubMed:26417687, ECO:0000269|PubMed:29494752,
CC ECO:0000269|PubMed:29884774}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=27.22 nM for ATP (for autophosphorylation reaction)
CC {ECO:0000269|PubMed:19366344};
CC Vmax=1.331 nmol/min/mg enzyme for autophosphorylation reaction
CC {ECO:0000269|PubMed:19366344};
CC Note=kcat is 0.000973 sec(-1) with ATP as substrate for
CC autophosphorylation reaction. {ECO:0000269|PubMed:19366344};
CC -!- SUBUNIT: Interacts with PtpA (PubMed:19366344, PubMed:22888002,
CC PubMed:29724125). The presence of a phosphate donor increases the
CC interaction affinity (PubMed:19366344). Interacts with TrxB
CC (PubMed:29317718). Interacts with several eukaryotic-like Ser/Thr
CC protein kinases (eSTPKs) in vivo, including PknA (PubMed:26417687).
CC {ECO:0000269|PubMed:19366344, ECO:0000269|PubMed:22888002,
CC ECO:0000269|PubMed:26417687, ECO:0000269|PubMed:29317718,
CC ECO:0000269|PubMed:29724125}.
CC -!- DOMAIN: Composed of two domains: the N-terminal highly flexible
CC intrinsically disordered domain (IDD) and the C-terminal rigid kinase
CC core domain (KCD) (PubMed:29494752, PubMed:29884774, PubMed:32157138).
CC IDD is unstructured and highly dynamic, allowing transient interactions
CC with the rigid KCD. This interaction modulates the accessibility of the
CC KCD active site (PubMed:29884774). In closed state, IDD masks the
CC autophosphorylation site, thereby decreasing the activity of PtkA. In
CC open state conformation, IDD is away from the autophosphorylation site,
CC making it accessible for phosphorylation and activation of PtkA
CC (PubMed:29884774). Phosphorylation of PtkA by serine/threonine kinase
CC induces conformational changes of IDD, which promotes the open state
CC (PubMed:29884774). IDD had a greater inhibitory effect on the catalytic
CC activity of KCD in the presence of the drugs esculin and inosine
CC pranobex (PubMed:32157138). {ECO:0000269|PubMed:29494752,
CC ECO:0000269|PubMed:29884774, ECO:0000269|PubMed:32157138}.
CC -!- PTM: Autophosphorylated (PubMed:19366344, PubMed:22888002,
CC PubMed:29884774). Can be phosphorylated in vitro on threonine residues
CC by several mycobacterial eukaryotic-like Ser/Thr protein kinases
CC (eSTPKs), including PknA, PknD, PknF and PknK. PknD and PknK can
CC enhance PtkA autophosphorylation activity in vitro (PubMed:26417687).
CC Phosphorylated in vitro on serine residues by the eukaryotic
CC serine/threonine kinase PKA (PubMed:29494752).
CC {ECO:0000269|PubMed:19366344, ECO:0000269|PubMed:22888002,
CC ECO:0000269|PubMed:26417687, ECO:0000269|PubMed:29494752,
CC ECO:0000269|PubMed:29884774}.
CC -!- DISRUPTION PHENOTYPE: Deletion mutant shows impaired intracellular
CC survival within the human THP-1 macrophage infection model, and fails
CC to inhibit phagosome acidification. However, the mutant displays
CC enhanced resistance against oxidative stress in vitro. Disruption of
CC the gene increases secretion of the thioredoxin reductase TrxB.
CC {ECO:0000269|PubMed:29317718}.
CC -!- BIOTECHNOLOGY: PtkA-PtpA (TK-TP) interaction could be a good target for
CC drug discovery program. Benzylbenzofurans and benzofuranamides disrupt
CC the PtkA-PtpA interaction, which inhibits activation of PtpA and leads
CC to the decrease in intracellular survival of mycobacteria.
CC {ECO:0000269|PubMed:29724125}.
CC -!- SIMILARITY: Belongs to the HAD-like hydrolase superfamily.
CC CbbY/CbbZ/Gph/YieH family. {ECO:0000305}.
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DR EMBL; AL123456; CCP45012.1; -; Genomic_DNA.
DR PIR; D70777; D70777.
DR RefSeq; NP_216748.2; NC_000962.3.
DR RefSeq; WP_003411507.1; NC_000962.3.
DR PDB; 6F2X; NMR; -; A=76-291.
DR PDBsum; 6F2X; -.
DR AlphaFoldDB; P9WPI9; -.
DR SMR; P9WPI9; -.
DR STRING; 83332.Rv2232; -.
DR PaxDb; P9WPI9; -.
DR GeneID; 887597; -.
DR KEGG; mtu:Rv2232; -.
DR PATRIC; fig|83332.111.peg.2486; -.
DR TubercuList; Rv2232; -.
DR eggNOG; COG0546; Bacteria.
DR OMA; YLCGKFG; -.
DR PhylomeDB; P9WPI9; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:MTBBASE.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MTBBASE.
DR DisProt; DP01160; -.
DR Gene3D; 1.10.150.240; -; 1.
DR Gene3D; 3.40.50.1000; -; 1.
DR InterPro; IPR036412; HAD-like_sf.
DR InterPro; IPR041492; HAD_2.
DR InterPro; IPR023214; HAD_sf.
DR InterPro; IPR023198; PGP-like_dom2.
DR Pfam; PF13419; HAD_2; 1.
DR SUPFAM; SSF56784; SSF56784; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Kinase; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Transferase; Tyrosine-protein kinase; Virulence.
FT CHAIN 1..291
FT /note="Tyrosine-protein kinase PtkA"
FT /id="PRO_0000108066"
FT REGION 1..79
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 18..61
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 262
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 85
FT /note="D->A: Significant decrease in ATP binding affinity
FT and autophosphorylation efficiency. Decreases interaction
FT with PtpA."
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 146
FT /note="Y->A: Does not affect autophosphorylation."
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 150
FT /note="Y->A: Does not affect autophosphorylation."
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 184
FT /note="K->M: Decreases affinity for ATP and
FT autophosphorylation efficiency."
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 217
FT /note="K->M: Decreases affinity for ATP and
FT autophosphorylation efficiency. Decreases interaction with
FT PtpA."
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 262
FT /note="Y->A: Lack of autophosphorylation. Decreases
FT interaction with PtpA. Cannot phosphorylate and activate
FT PtpA."
FT /evidence="ECO:0000269|PubMed:19366344,
FT ECO:0000269|PubMed:25535696"
FT MUTAGEN 270
FT /note="K->M: Decreases affinity for ATP and
FT autophosphorylation efficiency. Decreases interaction with
FT PtpA."
FT /evidence="ECO:0000269|PubMed:19366344"
FT STRAND 80..84
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 86..91
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 93..107
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 117..120
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 122..124
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 126..132
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 139..152
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 154..156
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 164..174
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 177..181
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 186..196
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 199..201
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 205..207
FT /evidence="ECO:0007829|PDB:6F2X"
FT TURN 216..218
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 219..227
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 235..241
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 242..250
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 254..258
FT /evidence="ECO:0007829|PDB:6F2X"
FT STRAND 277..279
FT /evidence="ECO:0007829|PDB:6F2X"
FT HELIX 282..289
FT /evidence="ECO:0007829|PDB:6F2X"
SQ SEQUENCE 291 AA; 30694 MW; 750F090FB154E6E5 CRC64;
MSSPRERRPA SQAPRLSRRP PAHQTSRSSP DTTAPTGSGL SNRFVNDNGI VTDTTASGTN
CPPPPRAAAR RASSPGESPQ LVIFDLDGTL TDSARGIVSS FRHALNHIGA PVPEGDLATH
IVGPPMHETL RAMGLGESAE EAIVAYRADY SARGWAMNSL FDGIGPLLAD LRTAGVRLAV
ATSKAEPTAR RILRHFGIEQ HFEVIAGAST DGSRGSKVDV LAHALAQLRP LPERLVMVGD
RSHDVDGAAA HGIDTVVVGW GYGRADFIDK TSTTVVTHAA TIDELREALG V
