PEPD_MYCTU
ID PEPD_MYCTU Reviewed; 464 AA.
AC O53896; I6Y5B5;
DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=Serine protease PepD {ECO:0000305};
DE EC=3.4.21.107 {ECO:0000269|PubMed:18479146};
DE AltName: Full=HtrA-like serine protease {ECO:0000303|PubMed:21445360};
GN Name=pepD {ECO:0000303|PubMed:20061478};
GN Synonyms=htrA2 {ECO:0000303|PubMed:18479146};
GN OrderedLocusNames=Rv0983 {ECO:0000312|EMBL:CCP43733.1};
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 FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, INDUCTION, DOMAIN, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP SER-317.
RC STRAIN=ATCC 27294 / TMC 102 / H37Rv;
RX PubMed=20061478; DOI=10.1128/jb.01167-09;
RA White M.J., He H., Penoske R.M., Twining S.S., Zahrt T.C.;
RT "PepD participates in the mycobacterial stress response mediated through
RT MprAB and SigE.";
RL J. Bacteriol. 192:1498-1510(2010).
RN [3]
RP FUNCTION, INTERACTION WITH PSPA/RV2744C, SUBCELLULAR LOCATION, AND DOMAIN.
RC STRAIN=ATCC 27294 / TMC 102 / H37Rv;
RX PubMed=21445360; DOI=10.1371/journal.pone.0018175;
RA White M.J., Savaryn J.P., Bretl D.J., He H., Penoske R.M., Terhune S.S.,
RA Zahrt T.C.;
RT "The HtrA-like serine protease PepD interacts with and modulates the
RT Mycobacterium tuberculosis 35-kDa antigen outer envelope protein.";
RL PLoS ONE 6:e18175-e18175(2011).
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 ACTIVITY REGULATION.
RX PubMed=23440996; DOI=10.4103/0250-474x.106063;
RA Daisy P., Vijayalakshmi P., Selvaraj C., Singh S.K., Saipriya K.;
RT "Targeting multidrug resistant Mycobacterium tuberculosis HtrA2 with
RT identical chemical entities of fluoroquinolones.";
RL Indian J. Pharm. Sci. 74:217-222(2012).
RN [6] {ECO:0007744|PDB:1Y8T}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 149-464.
RA Palaninathan S.K., Mohamedmohaideen N.N., Sacchettini J.C.;
RT "Possible role for HtrA homologs in mycobacterium tuberculosis.";
RL Submitted (DEC-2004) to the PDB data bank.
RN [7] {ECO:0007744|PDB:2Z9I}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 149-464 IN COMPLEX WITH
RP AUTOPROTEOLYTIC PEPTIDE FRAGMENTS, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, SUBUNIT, DOMAIN, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP SER-317.
RX PubMed=18479146; DOI=10.1021/bi701929m;
RA Mohamedmohaideen N.N., Palaninathan S.K., Morin P.M., Williams B.J.,
RA Braunstein M., Tichy S.E., Locker J., Russell D.H., Jacobs W.R.,
RA Sacchettini J.C.;
RT "Structure and function of the virulence-associated high-temperature
RT requirement A of Mycobacterium tuberculosis.";
RL Biochemistry 47:6092-6102(2008).
CC -!- FUNCTION: Required for virulence (PubMed:18479146). Acts both as a
CC protease, which degrades and/or refolds damaged substrate targets, and
CC as a chaperone (PubMed:18479146, PubMed:20061478). Plays an important
CC role in the stress response network mediated through the two-component
CC regulatory system MprAB and SigE signaling networks (PubMed:20061478).
CC May utilize its PDZ domain to recognize and process misfolded proteins
CC at the cell membrane, leading to activation of the MprAB and SigE
CC signaling pathways and subsequent establishment of a positive feedback
CC loop that facilitates bacterial adaptation (PubMed:20061478). Interacts
CC with and potentially cleaves several proteins, including the 35 kDa
CC antigen PspA (PubMed:21445360). Proteolytic cleavage of PspA may help
CC to maintain cell envelope homeostasis in Mycobacterium and regulate
CC specific stress response pathways during periods of extracytoplasmic
CC stress (PubMed:21445360). In vitro, exhibits proteolytic activity
CC against the artificial substrate beta-casein (PubMed:18479146,
CC PubMed:20061478). {ECO:0000269|PubMed:18479146,
CC ECO:0000269|PubMed:20061478, ECO:0000269|PubMed:21445360}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Acts on substrates that are at least partially unfolded. The
CC cleavage site P1 residue is normally between a pair of hydrophobic
CC residues, such as Val-|-Val.; EC=3.4.21.107;
CC Evidence={ECO:0000269|PubMed:18479146, ECO:0000269|PubMed:20061478};
CC -!- ACTIVITY REGULATION: Probably regulates its own activity by
CC autocleavage, which removes the PDZ domain (PubMed:18479146). Inhibited
CC by the serine protease inhibitor diisopropylfluorophosphate (DFP)
CC (PubMed:20061478). Inhibited by fluoroquinolone such as ciprofloxacin,
CC moxifloxacin and ofloxacin and their analogs (PubMed:23440996).
CC {ECO:0000269|PubMed:18479146, ECO:0000269|PubMed:20061478,
CC ECO:0000269|PubMed:23440996}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is between 7.0 and 8.5. {ECO:0000269|PubMed:20061478};
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius.
CC {ECO:0000269|PubMed:20061478};
CC -!- SUBUNIT: Homotrimer (PubMed:18479146). Interacts with numerous
CC proteins, including the 35 kDa antigen PspA (PubMed:21445360).
CC {ECO:0000269|PubMed:18479146, ECO:0000269|PubMed:21445360}.
CC -!- SUBCELLULAR LOCATION: Cell inner membrane
CC {ECO:0000269|PubMed:21445360}; Single-pass membrane protein
CC {ECO:0000255}. Secreted, cell wall {ECO:0000269|PubMed:21445360}.
CC Secreted {ECO:0000269|PubMed:21445360}. Note=Traffics from the
CC cytoplasm through the cell membrane to the cell wall where it is
CC autoprocessed and eventually secreted into the culture filtrate
CC protein. {ECO:0000269|PubMed:21445360}.
CC -!- INDUCTION: Transcribed from three distinct promoters, one that is
CC located in the intergenic region between mprB and pepD, one that
CC overlaps with the translational start site for mprA, and one upstream
CC of mprA that resides in a predicted SigE-regulated promoter region.
CC {ECO:0000269|PubMed:20061478}.
CC -!- DOMAIN: Each subunit is composed of an N-terminal cytoplasmic domain, a
CC transmembrane domain, a catalytic serine protease domain, and a single
CC C-terminal PDZ domain (PubMed:18479146, PubMed:21445360). The protease
CC domains form the central core of the trimer and the PDZ domains extend
CC to the periphery (PubMed:18479146). PDZ domain is required for protease
CC activity (PubMed:20061478). {ECO:0000269|PubMed:18479146,
CC ECO:0000269|PubMed:20061478, ECO:0000269|PubMed:21445360}.
CC -!- DISRUPTION PHENOTYPE: Deletion of the gene triggers a stress response
CC under physiological conditions that results in the up-regulation of a
CC number of gene products, including sigE, and a subset that are
CC regulated by SigE (PubMed:20061478). Deletion mutant shows attenuated
CC virulence in a mouse model of infection (PubMed:18479146).
CC {ECO:0000269|PubMed:18479146, ECO:0000269|PubMed:20061478}.
CC -!- SIMILARITY: Belongs to the peptidase S1C family. {ECO:0000305}.
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DR EMBL; AL123456; CCP43733.1; -; Genomic_DNA.
DR RefSeq; NP_215498.1; NC_000962.3.
DR RefSeq; WP_010886101.1; NZ_NVQJ01000018.1.
DR PDB; 1Y8T; X-ray; 2.00 A; A/B/C=149-464.
DR PDB; 2Z9I; X-ray; 2.00 A; A/B/C=149-464.
DR PDBsum; 1Y8T; -.
DR PDBsum; 2Z9I; -.
DR AlphaFoldDB; O53896; -.
DR SMR; O53896; -.
DR STRING; 83332.Rv0983; -.
DR MEROPS; S01.494; -.
DR PaxDb; O53896; -.
DR PRIDE; O53896; -.
DR DNASU; 885382; -.
DR GeneID; 885382; -.
DR KEGG; mtu:Rv0983; -.
DR PATRIC; fig|83332.111.peg.1091; -.
DR TubercuList; Rv0983; -.
DR eggNOG; COG0265; Bacteria.
DR InParanoid; O53896; -.
DR OMA; WRYATEQ; -.
DR PhylomeDB; O53896; -.
DR EvolutionaryTrace; O53896; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005576; C:extracellular region; IDA:MTBBASE.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro.
DR GO; GO:0008236; F:serine-type peptidase activity; IDA:MTBBASE.
DR GO; GO:0071236; P:cellular response to antibiotic; IMP:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IDA:MTBBASE.
DR GO; GO:0006508; P:proteolysis; IMP:UniProtKB.
DR Gene3D; 2.30.42.10; -; 1.
DR Gene3D; 2.40.10.10; -; 2.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR036034; PDZ_sf.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR InterPro; IPR001940; Peptidase_S1C.
DR Pfam; PF13180; PDZ_2; 1.
DR PRINTS; PR00834; PROTEASES2C.
DR SMART; SM00228; PDZ; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS50106; PDZ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell inner membrane; Cell membrane; Cell wall; Hydrolase;
KW Membrane; Protease; Reference proteome; Secreted; Serine protease;
KW Stress response; Transmembrane; Transmembrane helix.
FT CHAIN 1..464
FT /note="Serine protease PepD"
FT /id="PRO_0000450863"
FT TOPO_DOM 1..100
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:21445360"
FT TRANSMEM 101..121
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 122..464
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:21445360"
FT DOMAIN 368..449
FT /note="PDZ"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00143"
FT REGION 1..71
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 35..51
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 197
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P0C0V0"
FT ACT_SITE 236
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P0C0V0"
FT ACT_SITE 317
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P0C0V0"
FT MUTAGEN 317
FT /note="S->A: Loss of protease activity. Shows neither
FT autoproteolytic nor proteolytic activity against beta-
FT casein."
FT /evidence="ECO:0000269|PubMed:18479146,
FT ECO:0000269|PubMed:20061478"
FT HELIX 156..163
FT /evidence="ECO:0007829|PDB:1Y8T"
FT HELIX 164..166
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 167..173
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 180..185
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 190..195
FT /evidence="ECO:0007829|PDB:1Y8T"
FT HELIX 196..199
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 213..218
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 227..230
FT /evidence="ECO:0007829|PDB:1Y8T"
FT TURN 233..236
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 237..241
FT /evidence="ECO:0007829|PDB:1Y8T"
FT HELIX 256..258
FT /evidence="ECO:0007829|PDB:2Z9I"
FT STRAND 264..269
FT /evidence="ECO:0007829|PDB:1Y8T"
FT HELIX 271..273
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 277..290
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 303..308
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 319..322
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 326..335
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 353..357
FT /evidence="ECO:0007829|PDB:1Y8T"
FT HELIX 358..371
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 381..385
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 387..397
FT /evidence="ECO:0007829|PDB:1Y8T"
FT TURN 402..407
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 413..417
FT /evidence="ECO:0007829|PDB:1Y8T"
FT HELIX 425..433
FT /evidence="ECO:0007829|PDB:1Y8T"
FT STRAND 440..446
FT /evidence="ECO:0007829|PDB:1Y8T"
FT TURN 448..450
FT /evidence="ECO:0007829|PDB:2Z9I"
FT STRAND 452..458
FT /evidence="ECO:0007829|PDB:1Y8T"
SQ SEQUENCE 464 AA; 46453 MW; AE93BFCC53E1EC8F CRC64;
MAKLARVVGL VQEEQPSDMT NHPRYSPPPQ QPGTPGYAQG QQQTYSQQFD WRYPPSPPPQ
PTQYRQPYEA LGGTRPGLIP GVIPTMTPPP GMVRQRPRAG MLAIGAVTIA VVSAGIGGAA
ASLVGFNRAP AGPSGGPVAA SAAPSIPAAN MPPGSVEQVA AKVVPSVVML ETDLGRQSEE
GSGIILSAEG LILTNNHVIA AAAKPPLGSP PPKTTVTFSD GRTAPFTVVG ADPTSDIAVV
RVQGVSGLTP ISLGSSSDLR VGQPVLAIGS PLGLEGTVTT GIVSALNRPV STTGEAGNQN
TVLDAIQTDA AINPGNSGGA LVNMNAQLVG VNSAIATLGA DSADAQSGSI GLGFAIPVDQ
AKRIADELIS TGKASHASLG VQVTNDKDTL GAKIVEVVAG GAAANAGVPK GVVVTKVDDR
PINSADALVA AVRSKAPGAT VALTFQDPSG GSRTVQVTLG KAEQ
