SERB2_MYCTU
ID SERB2_MYCTU Reviewed; 409 AA.
AC O53289; I6X638;
DT 02-NOV-2016, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 137.
DE RecName: Full=Phosphoserine phosphatase SerB2 {ECO:0000303|PubMed:25037224, ECO:0000303|PubMed:25521849};
DE Short=PSP {ECO:0000303|PubMed:25037224, ECO:0000303|PubMed:25521849};
DE Short=PSPase;
DE EC=3.1.3.3 {ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849};
DE AltName: Full=O-phosphoserine phosphohydrolase {ECO:0000303|PubMed:25521849};
DE AltName: Full=Protein-serine/threonine phosphatase {ECO:0000305|PubMed:26984196};
DE EC=3.1.3.16 {ECO:0000269|PubMed:26984196};
GN Name=serB2 {ECO:0000303|PubMed:25037224, ECO:0000303|PubMed:25521849,
GN ECO:0000312|EMBL:CCP45851.1};
GN OrderedLocusNames=Rv3042c {ECO:0000312|EMBL:CCP45851.1};
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 DISRUPTION PHENOTYPE.
RC STRAIN=H37Rv;
RX PubMed=12657046; DOI=10.1046/j.1365-2958.2003.03425.x;
RA Sassetti C.M., Boyd D.H., Rubin E.J.;
RT "Genes required for mycobacterial growth defined by high density
RT mutagenesis.";
RL Mol. Microbiol. 48:77-84(2003).
RN [3]
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 [4]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES,
RP SUBSTRATE SPECIFICITY, ACTIVITY REGULATION, PATHWAY, 3D-STRUCTURE MODELING,
RP AND MUTAGENESIS OF ASP-185; VAL-186; SER-188; SER-273; LYS-318 AND ASP-341.
RC STRAIN=ATCC 27294 / TMC 102 / H37Rv;
RX PubMed=25037224; DOI=10.1074/jbc.m114.597682;
RA Arora G., Tiwari P., Mandal R.S., Gupta A., Sharma D., Saha S., Singh R.;
RT "High throughput screen identifies small molecule inhibitors specific for
RT Mycobacterium tuberculosis phosphoserine phosphatase.";
RL J. Biol. Chem. 289:25149-25165(2014).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES,
RP SUBSTRATE SPECIFICITY, ACTIVITY REGULATION, SUBUNIT, 3D-STRUCTURE MODELING,
RP DOMAIN, AND MUTAGENESIS OF GLY-18; GLY-108; ASP-185; ASP-187; SER-273;
RP LYS-318; ASP-341 AND ASP-345.
RX PubMed=25521849; DOI=10.1371/journal.pone.0115409;
RA Yadav G.P., Shree S., Maurya R., Rai N., Singh D.K., Srivastava K.K.,
RA Ramachandran R.;
RT "Characterization of M. tuberculosis SerB2, an essential HAD-family
RT phosphatase, reveals novel properties.";
RL PLoS ONE 9:E115409-E115409(2014).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACTIVITY REGULATION,
RP DRUG TARGET, AND MUTAGENESIS OF ASP-341 AND ASP-345.
RX PubMed=26984196; DOI=10.1007/s00018-016-2177-2;
RA Shree S., Singh A.K., Saxena R., Kumar H., Agarwal A., Sharma V.K.,
RA Srivastava K., Srivastava K.K., Sanyal S., Ramachandran R.;
RT "The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins
RT and is inhibited by Clofazimine.";
RL Cell. Mol. Life Sci. 73:3401-3417(2016).
CC -!- FUNCTION: Catalyzes the dephosphorylation of O-phospho-L-serine into L-
CC serine, a step in the L-serine biosynthetic pathway (PubMed:25037224,
CC PubMed:25521849). Exhibits high specificity for L-phosphoserine
CC compared to substrates like L-phosphothreonine (5% relative activity)
CC and L-phosphotyrosine (1.7% relative activity) (PubMed:25521849).
CC {ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849}.
CC -!- FUNCTION: In the host, induces significant cytoskeleton rearrangements
CC through cofilin dephosphorylation and its subsequent activation, and
CC affects the expression of genes that regulate actin dynamics. It
CC specifically interacts with HSP90, HSP70 and HSP27 that block apoptotic
CC pathways but not with other HSPs. Also interacts with GAPDH. It
CC actively dephosphorylates MAP kinase p38 and NF-kappa B p65
CC (specifically at Ser-536) that play crucial roles in inflammatory and
CC immune responses. This in turn leads to down-regulation of Interleukin
CC 8, a chemotactic and inflammatory cytokine. Thus might help the
CC pathogen to evade the host's immune response (PubMed:26984196).
CC Exogenous addition of purified SerB2 protein to human THP-1 cells (that
CC can be differentiated into macrophage-like cells) induces microtubule
CC rearrangements; the phosphatase activity is co-related to the elicited
CC rearrangements, while addition of the ACT-domains alone elicits no
CC rearrangements (PubMed:25521849). {ECO:0000269|PubMed:25521849,
CC ECO:0000269|PubMed:26984196}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-serine = L-serine + phosphate;
CC Xref=Rhea:RHEA:21208, ChEBI:CHEBI:15377, ChEBI:CHEBI:33384,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57524; EC=3.1.3.3;
CC Evidence={ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-D-serine = D-serine + phosphate;
CC Xref=Rhea:RHEA:24873, ChEBI:CHEBI:15377, ChEBI:CHEBI:35247,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58680; EC=3.1.3.3;
CC Evidence={ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:83421; EC=3.1.3.16;
CC Evidence={ECO:0000269|PubMed:26984196};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:61977; EC=3.1.3.16;
CC Evidence={ECO:0000269|PubMed:26984196};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849};
CC Note=Binds 1 Mg(2+) ion per subunit (By similarity). Can also use
CC Mn(2+) (PubMed:25037224, PubMed:25521849).
CC {ECO:0000250|UniProtKB:Q58989, ECO:0000269|PubMed:25037224,
CC ECO:0000269|PubMed:25521849};
CC -!- ACTIVITY REGULATION: Clofazimine, a drug being evaluated for XDR and
CC MDR tuberculosis, inhibits SerB2 phosphatase activity and reverses the
CC various functional effects described above and interactions with host
CC proteins (PubMed:26984196). Is inhibited by known PSP inhibitors such
CC as chlorpromazine, DL-AP3 and sodium orthovanadate, but not by okadaic
CC acid (PubMed:25037224, PubMed:25521849). By binding to the ACT domains,
CC amino-acids have various effects on enzyme activity: L-serine and L-
CC glycine act as inhibitors, whereas L-lysine, L-tyrosine and L-
CC phenylalanine are activators (PubMed:25521849). High throughput screen
CC has been performed to identify specific PSP inhibitors with activity
CC against intracellular bacteria; the two best hits identified in this
CC screen, clorobiocin and rosaniline, are bactericidal and kill bacteria
CC in infected macrophages in a dose-dependent manner (PubMed:25037224).
CC {ECO:0000269|PubMed:25037224, ECO:0000269|PubMed:25521849,
CC ECO:0000269|PubMed:26984196}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=92.68 uM for O-phospho-L-serine {ECO:0000269|PubMed:25037224};
CC KM=135.9 uM for O-phospho-L-serine {ECO:0000269|PubMed:25521849};
CC Vmax=14250 nmol/min/mg enzyme {ECO:0000269|PubMed:25521849};
CC Note=kcat is 8.83 min(-1) (PubMed:25037224). kcat is 25400 sec(-1)
CC (PubMed:25521849). {ECO:0000269|PubMed:25037224,
CC ECO:0000269|PubMed:25521849};
CC pH dependence:
CC Optimum pH is 7.5 (PubMed:25037224, PubMed:25521849). Activity
CC declines progressively before pH 7.5 and is almost abolished at 6.0
CC while at higher pH the enzyme remains active till pH 9.0
CC (PubMed:25521849). {ECO:0000269|PubMed:25037224,
CC ECO:0000269|PubMed:25521849};
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius. Activity declines at
CC higher temperatures and is completely abolished by 50 degrees
CC Celsius. {ECO:0000269|PubMed:25521849};
CC -!- PATHWAY: Amino-acid biosynthesis; L-serine biosynthesis; L-serine from
CC 3-phospho-D-glycerate: step 3/3. {ECO:0000305|PubMed:25037224}.
CC -!- SUBUNIT: Homodimer. The dimeric population shifts to a tetramer in the
CC presence of L-serine, which inactivates the enzyme.
CC {ECO:0000269|PubMed:25521849}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:26984196}. Host
CC cytoplasm, host cytosol {ECO:0000269|PubMed:26984196}. Note=Is secreted
CC into the cytosol of infected macrophages and is found in
CC bronchoalveolar lavage samples of tuberculosis patients. Co-localizes
CC with host tubulin. {ECO:0000269|PubMed:26984196}.
CC -!- DOMAIN: Folds into three domains, i.e. two ACT domains occurring in
CC tandem at the N-terminus followed by the classical phosphatase (PSP)
CC domain. The PSP domain alone is capable of hydrolyzing L-phosphoserine,
CC albeit with much reduced efficacy. The ACT domains are involved in
CC amino acid binding and play an important role in modulating enzymatic
CC activity. {ECO:0000269|PubMed:25521849}.
CC -!- DISRUPTION PHENOTYPE: Transposon mutagenesis experiments have
CC identified that SerB2 is essential for the pathogen's viability while
CC SerB1 is not. {ECO:0000269|PubMed:12657046}.
CC -!- SIMILARITY: Belongs to the HAD-like hydrolase superfamily. SerB family.
CC {ECO:0000305}.
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DR EMBL; AL123456; CCP45851.1; -; Genomic_DNA.
DR RefSeq; NP_217558.1; NC_000962.3.
DR RefSeq; WP_003912067.1; NZ_NVQJ01000011.1.
DR AlphaFoldDB; O53289; -.
DR SMR; O53289; -.
DR STRING; 83332.Rv3042c; -.
DR PaxDb; O53289; -.
DR DNASU; 887815; -.
DR GeneID; 887815; -.
DR KEGG; mtu:Rv3042c; -.
DR PATRIC; fig|83332.111.peg.3389; -.
DR TubercuList; Rv3042c; -.
DR eggNOG; COG0560; Bacteria.
DR eggNOG; COG3830; Bacteria.
DR InParanoid; O53289; -.
DR OMA; FAAHAGC; -.
DR PhylomeDB; O53289; -.
DR BRENDA; 3.1.3.3; 3445.
DR UniPathway; UPA00135; UER00198.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0044164; C:host cell cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0016597; F:amino acid binding; IDA:UniProtKB.
DR GO; GO:0036424; F:L-phosphoserine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IBA:GO_Central.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0016311; P:dephosphorylation; IDA:UniProtKB.
DR GO; GO:0006564; P:L-serine biosynthetic process; IBA:GO_Central.
DR GO; GO:0006470; P:protein dephosphorylation; IDA:UniProtKB.
DR Gene3D; 3.40.50.1000; -; 1.
DR InterPro; IPR045865; ACT-like_dom_sf.
DR InterPro; IPR002912; ACT_dom.
DR InterPro; IPR036412; HAD-like_sf.
DR InterPro; IPR023214; HAD_sf.
DR InterPro; IPR004469; PSP.
DR SFLD; SFLDF00029; phosphoserine_phosphatase; 1.
DR SUPFAM; SSF55021; SSF55021; 1.
DR SUPFAM; SSF56784; SSF56784; 1.
DR TIGRFAMs; TIGR00338; serB; 1.
DR PROSITE; PS51671; ACT; 1.
PE 1: Evidence at protein level;
KW Amino-acid biosynthesis; Host cytoplasm; Hydrolase; Magnesium;
KW Metal-binding; Reference proteome; Secreted; Serine biosynthesis.
FT CHAIN 1..409
FT /note="Phosphoserine phosphatase SerB2"
FT /id="PRO_0000437672"
FT DOMAIN 8..86
FT /note="ACT 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01007"
FT DOMAIN 102..174
FT /note="ACT 2"
FT /evidence="ECO:0000305|PubMed:25521849"
FT ACT_SITE 185
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT ACT_SITE 187
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 185
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 187
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 194
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 230
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 273..274
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 318
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 341
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT BINDING 344
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q58989"
FT MUTAGEN 18
FT /note="G->A: Does not bind L-serine and correspondingly no
FT oligomeric transitions is observed in the presence of L-
FT serine."
FT /evidence="ECO:0000269|PubMed:25521849"
FT MUTAGEN 108
FT /note="G->A: Does not bind L-serine and correspondingly no
FT oligomeric transitions is observed in the presence of L-
FT serine."
FT /evidence="ECO:0000269|PubMed:25521849"
FT MUTAGEN 185
FT /note="D->G: Completely abolishes enzymatic activity."
FT /evidence="ECO:0000269|PubMed:25037224"
FT MUTAGEN 185
FT /note="D->N: Completely abolishes enzymatic activity."
FT /evidence="ECO:0000269|PubMed:25521849"
FT MUTAGEN 186
FT /note="V->Q: Decreases enzymatic activity by 50%."
FT /evidence="ECO:0000269|PubMed:25037224"
FT MUTAGEN 187
FT /note="D->N: Decreases enzymatic activity by 15%."
FT /evidence="ECO:0000269|PubMed:25521849"
FT MUTAGEN 188
FT /note="S->A: No effect on enzymatic activity."
FT /evidence="ECO:0000269|PubMed:25037224"
FT MUTAGEN 273
FT /note="S->A: Completely abolishes enzymatic activity
FT (PubMed:25521849). Decreases enzymatic activity by 60%
FT (PubMed:25037224)."
FT /evidence="ECO:0000269|PubMed:25037224,
FT ECO:0000269|PubMed:25521849"
FT MUTAGEN 318
FT /note="K->A: Decreases enzymatic activity by 50%."
FT /evidence="ECO:0000269|PubMed:25521849"
FT MUTAGEN 318
FT /note="K->E: Completely abolishes enzymatic activity."
FT /evidence="ECO:0000269|PubMed:25037224"
FT MUTAGEN 341
FT /note="D->G: Decreases enzymatic activity by 80%."
FT /evidence="ECO:0000269|PubMed:25037224"
FT MUTAGEN 341
FT /note="D->N: Decreases enzymatic activity by 85%.
FT Completely abolishes enzymatic activity, does not elicit
FT cytoskeletal rearrangements, and does not suppress IL-8
FT production after TNF-alpha stimulation; when associated
FT with N-345."
FT /evidence="ECO:0000269|PubMed:25521849"
FT MUTAGEN 345
FT /note="D->N: Decreases enzymatic activity by 55%.
FT Completely abolishes enzymatic activity, does not elicit
FT cytoskeletal rearrangements, and does not suppress IL-8
FT production after TNF-alpha stimulation; when associated
FT with N-341."
FT /evidence="ECO:0000269|PubMed:25521849"
SQ SEQUENCE 409 AA; 43059 MW; A2D5C6A741A2EF89 CRC64;
MPAKVSVLIT VTGMDQPGVT SALFEVLAQH GVELLNVEQV VIRGRLTLGV LVSCPLDVAD
GTALRDDVAA AIHGVGLDVA IERSDDLPII RQPSTHTIFV LGRPITAGAF SAVARGVAAL
GVNIDFIRGI SDYPVTGLEL RVSVPPGCVG PLQIALTKVA AEEHVDVAVE DYGLAWRTKR
LIVFDVDSTL VQGEVIEMLA ARAGAQGQVA AITEAAMRGE LDFAESLQRR VATLAGLPAT
VIDDVAEQLE LMPGARTTIR TLRRLGFRCG VVSGGFRRII EPLARELMLD FVASNELEIV
DGILTGRVVG PIVDRPGKAK ALRDFASQYG VPMEQTVAVG DGANDIDMLG AAGLGIAFNA
KPALREVADA SLSHPYLDTV LFLLGVTRGE IEAADAGDCG VRRVEIPAD
