HIP1_MYCTU
ID HIP1_MYCTU Reviewed; 520 AA.
AC P9WHR3; L0TBN5; P65823; Q10509;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 25-MAY-2022, entry version 44.
DE RecName: Full=Serine protease Hip1 {ECO:0000303|PubMed:24830429};
DE EC=3.4.21.- {ECO:0000269|PubMed:24830429, ECO:0000269|PubMed:28346784};
DE AltName: Full=Hydrolase important for pathogenesis 1 {ECO:0000303|PubMed:21947769};
DE AltName: Full=Serine hydrolase Hip1 {ECO:0000303|PubMed:21947769};
DE Flags: Precursor;
GN Name=hip1 {ECO:0000303|PubMed:21947769};
GN Synonyms=caeA {ECO:0000303|PubMed:27690385}; OrderedLocusNames=Rv2224c;
GN ORFNames=MTCY427.05c;
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, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP CYS-31 AND SER-228.
RX PubMed=18172199; DOI=10.1073/pnas.0710601105;
RA Rengarajan J., Murphy E., Park A., Krone C.L., Hett E.C., Bloom B.R.,
RA Glimcher L.H., Rubin E.J.;
RT "Mycobacterium tuberculosis Rv2224c modulates innate immune responses.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:264-269(2008).
RN [3]
RP DISRUPTION PHENOTYPE.
RX PubMed=19011036; DOI=10.1128/jb.00932-08;
RA Vandal O.H., Roberts J.A., Odaira T., Schnappinger D., Nathan C.F.,
RA Ehrt S.;
RT "Acid-susceptible mutants of Mycobacterium tuberculosis share
RT hypersusceptibility to cell wall and oxidative stress and to the host
RT environment.";
RL J. Bacteriol. 191:625-631(2009).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=H37Rv;
RX PubMed=21947769; DOI=10.1128/iai.05574-11;
RA Madan-Lala R., Peixoto K.V., Re F., Rengarajan J.;
RT "Mycobacterium tuberculosis Hip1 dampens macrophage proinflammatory
RT responses by limiting toll-like receptor 2 activation.";
RL Infect. Immun. 79:4828-4838(2011).
RN [5]
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 [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=H37Rv;
RX PubMed=24659689; DOI=10.4049/jimmunol.1303185;
RA Madan-Lala R., Sia J.K., King R., Adekambi T., Monin L., Khader S.A.,
RA Pulendran B., Rengarajan J.;
RT "Mycobacterium tuberculosis impairs dendritic cell functions through the
RT serine hydrolase Hip1.";
RL J. Immunol. 192:4263-4272(2014).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, INTERACTION WITH GROEL2,
RP DISRUPTION PHENOTYPE, AND MUTAGENESIS OF SER-228.
RX PubMed=24830429; DOI=10.1371/journal.ppat.1004132;
RA Naffin-Olivos J.L., Georgieva M., Goldfarb N., Madan-Lala R., Dong L.,
RA Bizzell E., Valinetz E., Brandt G.S., Yu S., Shabashvili D.E., Ringe D.,
RA Dunn B.M., Petsko G.A., Rengarajan J.;
RT "Mycobacterium tuberculosis Hip1 modulates macrophage responses through
RT proteolysis of GroEL2.";
RL PLoS Pathog. 10:e1004132-e1004132(2014).
RN [8]
RP DEVELOPMENTAL STAGE.
RX PubMed=27690385; DOI=10.1021/acsinfecdis.6b00135;
RA Tallman K.R., Levine S.R., Beatty K.E.;
RT "Small-molecule probes reveal esterases with persistent activity in dormant
RT and reactivating Mycobacterium tuberculosis.";
RL ACS Infect. Dis. 2:936-944(2016).
RN [9] {ECO:0007744|PDB:5UGQ, ECO:0007744|PDB:5UNO, ECO:0007744|PDB:5UOH}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 50-520 OF WILD-TYPE AND MUTANT
RP ALA-466, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP DOMAIN, DISULFIDE BOND, ACTIVE SITE, AND MUTAGENESIS OF SER-228 AND
RP THR-466.
RX PubMed=28346784; DOI=10.1021/acs.biochem.6b01066;
RA Naffin-Olivos J.L., Daab A., White A., Goldfarb N.E., Milne A.C., Liu D.,
RA Baikovitz J., Dunn B.M., Rengarajan J., Petsko G.A., Ringe D.;
RT "Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1
RT (Rv2224c).";
RL Biochemistry 56:2304-2314(2017).
CC -!- FUNCTION: Serine protease that promotes tuberculosis (TB) pathogenesis
CC by promoting the processing and the extracellular release of the
CC M.tuberculosis (Mtb) heat-shock protein GroEL2 (PubMed:18172199,
CC PubMed:24830429, PubMed:28346784). Hip1-dependent cleavage of
CC multimeric GroEL2 results in release of cleaved monomeric GroEL2 into
CC the extracellular milieu. Conversion of multimeric GroEL2 into
CC monomeric GroEL2 is likely to be a mechanism for regulating GroEL2
CC functions during Mtb pathogenesis (PubMed:24830429). In vitro, exhibits
CC proteolytic activity against synthetic peptides and the general
CC protease substrate azocasein, and exhibits esterase activity against
CC the ester substrate p-nitrophenylbutyrate (PubMed:24830429,
CC PubMed:28346784). {ECO:0000269|PubMed:18172199,
CC ECO:0000269|PubMed:24830429, ECO:0000269|PubMed:28346784}.
CC -!- FUNCTION: Key immunomodulatory virulence factor, which promotes
CC survival in host macrophages and modulates host immune responses
CC (PubMed:18172199, PubMed:21947769, PubMed:24659689). Impacts host
CC innate immune responses by preventing robust macrophage activation
CC (PubMed:18172199, PubMed:21947769). Dampens macrophage pro-inflammatory
CC responses by limiting toll-like receptor 2 (TLR2) activation. It also
CC dampens TLR2-independent activation of the inflammasome and limits
CC secretion of interleukin-18 (IL-18). May act by masking cell surface
CC interactions between TLR2 agonists on Mtb and TLR2 on macrophages
CC (PubMed:21947769). In addition, impacts host adaptive immune responses.
CC It prevents robust maturation of infected dendritic cells (DCs), limits
CC the secretion of key pro-inflammatory cytokines such as IL-12, impairs
CC Ag presentation, and modulates the nature of Ag-specific T-cell
CC responses (PubMed:24659689). {ECO:0000269|PubMed:18172199,
CC ECO:0000269|PubMed:21947769, ECO:0000269|PubMed:24659689}.
CC -!- ACTIVITY REGULATION: Protease activity is inhibited by serine protease
CC inhibitors but not by cysteine protease inhibitors.
CC {ECO:0000269|PubMed:24830429}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.19 mM for GroEL2 {ECO:0000269|PubMed:28346784};
CC Note=kcat is 0.45 min(-1) with GroEL2 as substrate.
CC {ECO:0000269|PubMed:28346784};
CC -!- SUBUNIT: Interacts with GroEL2. {ECO:0000269|PubMed:24830429}.
CC -!- SUBCELLULAR LOCATION: Cell envelope {ECO:0000269|PubMed:18172199}. Cell
CC membrane {ECO:0000255|PROSITE-ProRule:PRU00303,
CC ECO:0000269|PubMed:18172199}; Lipid-anchor {ECO:0000255|PROSITE-
CC ProRule:PRU00303}.
CC -!- DEVELOPMENTAL STAGE: Shows esterase activity in active, dormant, and
CC reactivating Mtb cultures. {ECO:0000269|PubMed:27690385}.
CC -!- DOMAIN: The active site region is accessed through a large opening that
CC suggests that the enzyme has endopeptidase activity rather than
CC exopeptidase activity. {ECO:0000269|PubMed:28346784}.
CC -!- DISRUPTION PHENOTYPE: Disruption of the gene leads to growth defects
CC and attenuates the virulence of Mtb (PubMed:18172199, PubMed:19011036).
CC Disruption of the gene enhances host innate immune responses,
CC compromises the intracellular survival of Mtb in macrophages, and
CC increases its susceptibility to lysozyme. It prolongs survival and
CC reduces lung immunopathology of infected mice (PubMed:18172199).
CC Disruption leads to earlier and significantly higher levels of key pro-
CC inflammatory cytokines and chemokines (PubMed:21947769). Mutant induces
CC enhanced levels of the key Th1-inducing cytokine IL-12, as well as
CC other pro-inflammatory cytokines (IL-23, IL-6, TNF-alpha, IL-1beta, and
CC IL-18) in DCs via MyD88- and TLR2/9-dependent pathways
CC (PubMed:24659689). Infection with the hip1 mutant also induces higher
CC levels of MHC class II and costimulatory molecules CD40 and CD86
CC (PubMed:24659689). At low pH, mutants are hypersensitive to
CC antibiotics, sodium dodecyl sulfate, heat shock, and reactive oxygen
CC and nitrogen intermediates (PubMed:19011036). GroEL2 remains uncleaved
CC in the hip1 mutant (PubMed:24830429). {ECO:0000269|PubMed:18172199,
CC ECO:0000269|PubMed:19011036, ECO:0000269|PubMed:21947769,
CC ECO:0000269|PubMed:24659689, ECO:0000269|PubMed:24830429}.
CC -!- MISCELLANEOUS: Hip1 is an attractive target for developing
CC immunomodulatory therapeutics against Mtb.
CC {ECO:0000269|PubMed:24830429}.
CC -!- SIMILARITY: Belongs to the peptidase S33 family. {ECO:0000305}.
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DR EMBL; AL123456; CCP45002.1; -; Genomic_DNA.
DR PIR; D70776; D70776.
DR RefSeq; NP_216740.1; NC_000962.3.
DR RefSeq; WP_003411486.1; NZ_NVQJ01000008.1.
DR PDB; 5UGQ; X-ray; 2.61 A; A=50-520.
DR PDB; 5UNO; X-ray; 2.60 A; A=50-520.
DR PDB; 5UOH; X-ray; 2.61 A; A=50-520.
DR PDBsum; 5UGQ; -.
DR PDBsum; 5UNO; -.
DR PDBsum; 5UOH; -.
DR AlphaFoldDB; P9WHR3; -.
DR SMR; P9WHR3; -.
DR STRING; 83332.Rv2224c; -.
DR ESTHER; myctu-ym24; AlphaBeta_hydrolase.
DR MEROPS; S33.023; -.
DR PaxDb; P9WHR3; -.
DR GeneID; 45426201; -.
DR GeneID; 887857; -.
DR KEGG; mtu:Rv2224c; -.
DR PATRIC; fig|83332.111.peg.2473; -.
DR TubercuList; Rv2224c; -.
DR eggNOG; COG0596; Bacteria.
DR OMA; LNCAYWP; -.
DR PhylomeDB; P9WHR3; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; HDA:MTBBASE.
DR GO; GO:0031975; C:envelope; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; IDA:MTBBASE.
DR GO; GO:0052689; F:carboxylic ester hydrolase activity; IDA:MTBBASE.
DR GO; GO:0043687; P:post-translational protein modification; IMP:MTBBASE.
DR GO; GO:0052572; P:response to host immune response; IEP:MTBBASE.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR000073; AB_hydrolase_1.
DR Pfam; PF00561; Abhydrolase_1; 1.
DR SUPFAM; SSF53474; SSF53474; 1.
DR PROSITE; PS51257; PROKAR_LIPOPROTEIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Disulfide bond; Hydrolase; Lipoprotein;
KW Membrane; Palmitate; Reference proteome; Signal; Virulence.
FT SIGNAL 1..30
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00303"
FT CHAIN 31..520
FT /note="Serine protease Hip1"
FT /id="PRO_0000027329"
FT DOMAIN 102..497
FT /note="AB hydrolase-1"
FT /evidence="ECO:0000255"
FT ACT_SITE 228
FT /note="Nucleophile"
FT /evidence="ECO:0000305|PubMed:28346784"
FT ACT_SITE 463
FT /evidence="ECO:0000305|PubMed:28346784"
FT ACT_SITE 490
FT /note="Proton donor"
FT /evidence="ECO:0000305|PubMed:28346784"
FT LIPID 31
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00303"
FT LIPID 31
FT /note="S-diacylglycerol cysteine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00303"
FT DISULFID 55..70
FT /evidence="ECO:0000269|PubMed:28346784,
FT ECO:0007744|PDB:5UGQ, ECO:0007744|PDB:5UNO,
FT ECO:0007744|PDB:5UOH"
FT DISULFID 153..189
FT /evidence="ECO:0000269|PubMed:28346784,
FT ECO:0007744|PDB:5UGQ, ECO:0007744|PDB:5UNO,
FT ECO:0007744|PDB:5UOH"
FT DISULFID 282..288
FT /evidence="ECO:0000269|PubMed:28346784,
FT ECO:0007744|PDB:5UGQ, ECO:0007744|PDB:5UNO,
FT ECO:0007744|PDB:5UOH"
FT DISULFID 393..433
FT /evidence="ECO:0000269|PubMed:28346784,
FT ECO:0007744|PDB:5UGQ, ECO:0007744|PDB:5UNO,
FT ECO:0007744|PDB:5UOH"
FT DISULFID 499..520
FT /evidence="ECO:0000269|PubMed:28346784,
FT ECO:0007744|PDB:5UGQ, ECO:0007744|PDB:5UNO,
FT ECO:0007744|PDB:5UOH"
FT MUTAGEN 31
FT /note="C->A: Cannot cleave GroEL2."
FT /evidence="ECO:0000269|PubMed:18172199"
FT MUTAGEN 228
FT /note="S->A: Cannot complement the growth defect of the
FT disruption mutant. Cannot cleave GroEL2. Is unable to
FT hydrolyze azocasein."
FT /evidence="ECO:0000269|PubMed:18172199,
FT ECO:0000269|PubMed:24830429, ECO:0000269|PubMed:28346784"
FT MUTAGEN 466
FT /note="T->A: Small decrease in activity with azocasein as
FT substrate. Almost abolishes cleavage of GroEL2."
FT /evidence="ECO:0000269|PubMed:28346784"
FT STRAND 69..78
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 81..84
FT /evidence="ECO:0007829|PDB:5UGQ"
FT STRAND 86..94
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 97..99
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 102..107
FT /evidence="ECO:0007829|PDB:5UNO"
FT TURN 110..112
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 115..125
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 128..133
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 134..140
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 147..149
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 156..164
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 172..198
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 203..216
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 220..227
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 230..240
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 242..244
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 245..252
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 260..282
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 294..296
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 297..305
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 306..308
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 323..326
FT /evidence="ECO:0007829|PDB:5UGQ"
FT HELIX 330..340
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 344..346
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 347..358
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 363..373
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 384..395
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 402..415
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 417..419
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 432..435
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 456..460
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 464..466
FT /evidence="ECO:0007829|PDB:5UNO"
FT HELIX 468..478
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 481..485
FT /evidence="ECO:0007829|PDB:5UNO"
FT STRAND 487..490
FT /evidence="ECO:0007829|PDB:5UNO"
FT TURN 493..496
FT /evidence="ECO:0007829|PDB:5UOH"
FT HELIX 498..509
FT /evidence="ECO:0007829|PDB:5UNO"
SQ SEQUENCE 520 AA; 55924 MW; 8DC560534ABE9B0E CRC64;
MGMRLSRRDK IARMLLIWAA LAAVALVLVG CIRVVGGRAR MAEPKLGQPV EWTPCRSSNP
QVKIPGGALC GKLAVPVDYD RPDGDVAALA LIRFPATGDK IGSLVINPGG PGESGIEAAL
GVFQTLPKRV HERFDLVGFD PRGVASSRPA IWCNSDADND RLRAEPQVDY SREGVAHIEN
ETKQFVGRCV DKMGKNFLAH VGTVNVAKDL DAIRAALGDD KLTYLGYSYG TRIGSAYAEE
FPQRVRAMIL DGAVDPNADP IEAELRQAKG FQDAFNNYAA DCAKNAGCPL GADPAKAVEV
YHSLVDPLVD PDNPRISRPA RTKDPRGLSY SDAIVGTIMA LYSPNLWQHL TDGLSELVDN
RGDTLLALAD MYMRRDSHGR YNNSGDARVA INCVDQPPVT DRDKVIDEDR RAREIAPFMS
YGKFTGDAPL GTCAFWPVPP TSQPHAVSAP GLVPTVVVST THDPATPYKA GVDLANQLRG
SLLTFDGTQH TVVFQGDSCI DEYVTAYLIG GTTPPSGAKC
