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PPEP1_CLOD6
ID   PPEP1_CLOD6             Reviewed;         220 AA.
AC   Q183R7;
DT   09-JUL-2014, integrated into UniProtKB/Swiss-Prot.
DT   25-JUL-2006, sequence version 1.
DT   03-AUG-2022, entry version 84.
DE   RecName: Full=Pro-Pro endopeptidase {ECO:0000303|PubMed:26522134};
DE            Short=PPEP-1 {ECO:0000303|PubMed:26522134};
DE            EC=3.4.24.89 {ECO:0000269|PubMed:24623589, ECO:0000269|PubMed:26522134};
DE   AltName: Full=Zinc metalloprotease Zmp1 {ECO:0000303|PubMed:24303041};
DE   Flags: Precursor;
GN   Name=zmp1 {ECO:0000303|PubMed:24303041};
GN   Synonyms=ppep-1 {ECO:0000303|PubMed:29794027};
GN   OrderedLocusNames=CD630_28300;
OS   Clostridioides difficile (strain 630) (Peptoclostridium difficile).
OC   Bacteria; Firmicutes; Clostridia; Eubacteriales; Peptostreptococcaceae;
OC   Clostridioides.
OX   NCBI_TaxID=272563;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=630;
RX   PubMed=16804543; DOI=10.1038/ng1830;
RA   Sebaihia M., Wren B.W., Mullany P., Fairweather N.F., Minton N.,
RA   Stabler R., Thomson N.R., Roberts A.P., Cerdeno-Tarraga A.M., Wang H.,
RA   Holden M.T.G., Wright A., Churcher C., Quail M.A., Baker S., Bason N.,
RA   Brooks K., Chillingworth T., Cronin A., Davis P., Dowd L., Fraser A.,
RA   Feltwell T., Hance Z., Holroyd S., Jagels K., Moule S., Mungall K.,
RA   Price C., Rabbinowitsch E., Sharp S., Simmonds M., Stevens K., Unwin L.,
RA   Whithead S., Dupuy B., Dougan G., Barrell B., Parkhill J.;
RT   "The multidrug-resistant human pathogen Clostridium difficile has a highly
RT   mobile, mosaic genome.";
RL   Nat. Genet. 38:779-786(2006).
RN   [2]
RP   INDUCTION.
RC   STRAIN=630;
RX   PubMed=23675309; DOI=10.1371/journal.pgen.1003493;
RA   Soutourina O.A., Monot M., Boudry P., Saujet L., Pichon C., Sismeiro O.,
RA   Semenova E., Severinov K., Le Bouguenec C., Coppee J.Y., Dupuy B.,
RA   Martin-Verstraete I.;
RT   "Genome-wide identification of regulatory RNAs in the human pathogen
RT   Clostridium difficile.";
RL   PLoS Genet. 9:E1003493-E1003493(2013).
RN   [3]
RP   IDENTIFICATION BY MASS SPECTROMETRY, GENE NAME, FUNCTION, COFACTOR,
RP   SUBSTRATE SPECIFICITY, SUBCELLULAR LOCATION, ACTIVE SITE, AND MUTAGENESIS
RP   OF GLU-143 AND HIS-146.
RC   STRAIN=630;
RX   PubMed=24303041; DOI=10.1371/journal.pone.0081306;
RA   Cafardi V., Biagini M., Martinelli M., Leuzzi R., Rubino J.T., Cantini F.,
RA   Norais N., Scarselli M., Serruto D., Unnikrishnan M.;
RT   "Identification of a novel zinc metalloprotease through a global analysis
RT   of Clostridium difficile extracellular proteins.";
RL   PLoS ONE 8:E81306-E81306(2013).
RN   [4]
RP   IDENTIFICATION BY MASS SPECTROMETRY, FUNCTION, CATALYTIC ACTIVITY,
RP   COFACTOR, SUBSTRATE SPECIFICITY, CLEAVAGE MOTIF, KINETIC PARAMETERS,
RP   ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RC   STRAIN=630;
RX   PubMed=24623589; DOI=10.1074/mcp.m113.034728;
RA   Hensbergen P.J., Klychnikov O.I., Bakker D., van Winden V.J., Ras N.,
RA   Kemp A.C., Cordfunke R.A., Dragan I., Deelder A.M., Kuijper E.J.,
RA   Corver J., Drijfhout J.W., van Leeuwen H.C.;
RT   "A novel secreted metalloprotease (CD2830) from Clostridium difficile
RT   cleaves specific proline sequences in LPXTG cell surface proteins.";
RL   Mol. Cell. Proteomics 13:1231-1244(2014).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, DISRUPTION PHENOTYPE,
RP   AND SUBCELLULAR LOCATION.
RC   STRAIN=630;
RX   PubMed=26522134; DOI=10.1016/j.febslet.2015.10.027;
RA   Hensbergen P.J., Klychnikov O.I., Bakker D., Dragan I., Kelly M.L.,
RA   Minton N.P., Corver J., Kuijper E.J., Drijfhout J.W., van Leeuwen H.C.;
RT   "Clostridium difficile secreted Pro-Pro endopeptidase PPEP-1 (ZMP1/CD2830)
RT   modulates adhesion through cleavage of the collagen binding protein
RT   CD2831.";
RL   FEBS Lett. 589:3952-3958(2015).
RN   [6]
RP   FUNCTION.
RC   STRAIN=630;
RX   PubMed=26283789; DOI=10.1074/jbc.m115.665091;
RA   Peltier J., Shaw H.A., Couchman E.C., Dawson L.F., Yu L., Choudhary J.S.,
RA   Kaever V., Wren B.W., Fairweather N.F.;
RT   "Cyclic diGMP regulates production of sortase substrates of Clostridium
RT   difficile and their surface exposure through ZmpI protease-mediated
RT   cleavage.";
RL   J. Biol. Chem. 290:24453-24469(2015).
RN   [7]
RP   REVIEW.
RX   PubMed=28636257; DOI=10.1111/mmi.13736;
RA   Corver J., Cordo' V., van Leeuwen H.C., Klychnikov O.I., Hensbergen P.J.;
RT   "Covalent attachment and Pro-Pro endopeptidase (PPEP-1)-mediated release of
RT   Clostridium difficile cell surface proteins involved in adhesion.";
RL   Mol. Microbiol. 105:663-673(2017).
RN   [8]
RP   SUBUNIT, AND MUTAGENESIS OF 117-GLY--THR-120.
RC   STRAIN=630;
RX   PubMed=29794027; DOI=10.1074/jbc.ra118.003244;
RA   Klychnikov O.I., Shamorkina T.M., Weeks S.D., van Leeuwen H.C., Corver J.,
RA   Drijfhout J.W., van Veelen P.A., Sluchanko N.N., Strelkov S.V.,
RA   Hensbergen P.J.;
RT   "Discovery of a new Pro-Pro endopeptidase, PPEP-2, provides mechanistic
RT   insights into the differences in substrate specificity within the PPEP
RT   family.";
RL   J. Biol. Chem. 293:11154-11165(2018).
RN   [9]
RP   X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) OF 27-220 OF WILD-TYPE AND MUTANTS
RP   ALA-143 AND ALA-143/PHE-178 IN COMPLEXES WITH ZINC AND SUBSTRATE PEPTIDE,
RP   ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF GLU-143 AND TYR-178.
RC   STRAIN=630;
RX   PubMed=26211609; DOI=10.1016/j.str.2015.06.018;
RA   Schacherl M., Pichlo C., Neundorf I., Baumann U.;
RT   "Structural basis of proline-proline peptide bond specificity of the
RT   metalloprotease Zmp1 implicated in motility of Clostridium difficile.";
RL   Structure 23:1632-1642(2015).
CC   -!- FUNCTION: Zinc-dependent endoprotease with a unique preference for
CC       proline residues surrounding the scissile bond. Exhibits a high
CC       preference for an asparagine at the P2 position and hydrophobic
CC       residues (Val, Ile, Leu) at the P3 position. Efficiently cleaves the
CC       LPXTG cell surface proteins CD630_28310 and CD630_32460 at multiple
CC       cleavage sites in vivo. Has a role in the regulation of C.difficile
CC       adhesion versus motility by cleaving surface adhesion proteins such as
CC       the collagen binding protein CD630_28310, and is important for
CC       efficient infection. Is also able to cleave fibronectin and fibrinogen
CC       in vitro; cleaves at the N-terminus of the beta-chain of fibrinogen.
CC       Destabilizes the fibronectin network produced by human fibroblasts.
CC       Therefore, may be important in key steps of clostridial pathogenesis by
CC       degrading extracellular matrix components associated with the gut
CC       epithelial cells. To a lesser extent, IgA1, IgA2, and human HSP 90-
CC       beta, but not HSP 90-alpha, are also substrates for the enzyme. Is not
CC       active on different collagen types, casein and gelatin.
CC       {ECO:0000269|PubMed:24303041, ECO:0000269|PubMed:24623589,
CC       ECO:0000269|PubMed:26283789, ECO:0000269|PubMed:26522134}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=The enzyme catalyzes the hydrolytic cleavage of peptide bonds
CC         between two proline residues.; EC=3.4.24.89;
CC         Evidence={ECO:0000269|PubMed:24623589, ECO:0000269|PubMed:26522134};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000255|PROSITE-ProRule:PRU01339,
CC         ECO:0000269|PubMed:24303041, ECO:0000269|PubMed:24623589};
CC       Note=Binds 1 zinc ion per subunit. {ECO:0000255|PROSITE-
CC       ProRule:PRU01339, ECO:0000269|PubMed:24303041,
CC       ECO:0000269|PubMed:24623589, ECO:0000269|PubMed:26211609};
CC   -!- ACTIVITY REGULATION: Is inhibited by the chelating agent o-
CC       phenanthroline in vitro. {ECO:0000269|PubMed:24623589}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=77 uM for synthetic FRET peptide DabcylLys-EVNPPPPD-EdansGlu
CC         {ECO:0000269|PubMed:24623589};
CC         Vmax=0.08 nmol/sec/ug enzyme with synthetic FRET peptide DabcylLys-
CC         EVNPPPPD-EdansGlu as substrate {ECO:0000269|PubMed:24623589};
CC         Note=kcat is 19 sec(-1) with synthetic FRET peptide DabcylLys-
CC         EVNPPPPD-EdansGlu as substrate. {ECO:0000269|PubMed:24623589};
CC   -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:29794027}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:24303041,
CC       ECO:0000269|PubMed:24623589, ECO:0000269|PubMed:26522134}.
CC   -!- INDUCTION: Expression is controlled by a type I c-diGMP riboswitch;
CC       elevated levels of c-diGMP repress transcription of zmp1.
CC       {ECO:0000269|PubMed:23675309}.
CC   -!- DOMAIN: The structure of Zmp1 is similar to anthrax lethal factor (LF)
CC       metalloprotease domain IV. The S-loop of Zmp1 undergoes large motions
CC       upon substrate binding and seems to exhibit a function analogous to
CC       that of LF domain III, thus contributing to sequence specificity and
CC       substrate binding. An aliphatic-aromatic network and the diverting loop
CC       contribute to Pro-Pro specificity. {ECO:0000269|PubMed:26211609}.
CC   -!- DISRUPTION PHENOTYPE: Cells lacking this gene retain CD630_28310 on the
CC       cell surface, show higher affinity for collagen type I with attenuated
CC       virulence in a hamster model of infection.
CC       {ECO:0000269|PubMed:26522134}.
CC   -!- SIMILARITY: Belongs to the peptidase M34 family. Pro-Pro endopeptidase
CC       subfamily. {ECO:0000305}.
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DR   EMBL; AM180355; CAJ69718.1; -; Genomic_DNA.
DR   RefSeq; WP_011861706.1; NZ_CP010905.2.
DR   RefSeq; YP_001089343.1; NC_009089.1.
DR   PDB; 2N6J; NMR; -; A=27-220.
DR   PDB; 5A0P; X-ray; 1.40 A; A/B=27-220.
DR   PDB; 5A0R; X-ray; 1.25 A; A/B=27-220.
DR   PDB; 5A0S; X-ray; 2.56 A; A/B=27-220.
DR   PDB; 5A0X; X-ray; 1.70 A; A/B=27-220.
DR   PDB; 5N12; X-ray; 1.38 A; A/B=27-220.
DR   PDB; 6R4W; X-ray; 1.39 A; A/B=27-220.
DR   PDB; 6R4X; X-ray; 1.83 A; A/B=27-220.
DR   PDB; 6R4Y; X-ray; 1.45 A; A/B=27-220.
DR   PDB; 6R4Z; X-ray; 1.05 A; A/B=27-220.
DR   PDB; 6R50; X-ray; 1.81 A; A/B=27-220.
DR   PDB; 6R51; X-ray; 1.94 A; A/B/C=27-220.
DR   PDB; 6R52; X-ray; 2.02 A; A/B=24-220.
DR   PDB; 6R53; X-ray; 1.80 A; A/B=24-220.
DR   PDB; 6R54; X-ray; 1.42 A; A/B=27-220.
DR   PDB; 6R55; X-ray; 1.40 A; A/B=27-220.
DR   PDB; 6R56; X-ray; 1.77 A; A/B=27-220.
DR   PDB; 6R57; X-ray; 1.90 A; A/B=27-220.
DR   PDB; 6R58; X-ray; 1.90 A; A/B/C/D=27-220.
DR   PDB; 6R59; X-ray; 1.65 A; A/B=27-220.
DR   PDB; 6R5A; X-ray; 1.48 A; A/B=24-220.
DR   PDB; 6R5B; X-ray; 2.06 A; A/B=27-220.
DR   PDB; 6R5C; X-ray; 1.88 A; A/B=27-220.
DR   PDBsum; 2N6J; -.
DR   PDBsum; 5A0P; -.
DR   PDBsum; 5A0R; -.
DR   PDBsum; 5A0S; -.
DR   PDBsum; 5A0X; -.
DR   PDBsum; 5N12; -.
DR   PDBsum; 6R4W; -.
DR   PDBsum; 6R4X; -.
DR   PDBsum; 6R4Y; -.
DR   PDBsum; 6R4Z; -.
DR   PDBsum; 6R50; -.
DR   PDBsum; 6R51; -.
DR   PDBsum; 6R52; -.
DR   PDBsum; 6R53; -.
DR   PDBsum; 6R54; -.
DR   PDBsum; 6R55; -.
DR   PDBsum; 6R56; -.
DR   PDBsum; 6R57; -.
DR   PDBsum; 6R58; -.
DR   PDBsum; 6R59; -.
DR   PDBsum; 6R5A; -.
DR   PDBsum; 6R5B; -.
DR   PDBsum; 6R5C; -.
DR   AlphaFoldDB; Q183R7; -.
DR   BMRB; Q183R7; -.
DR   SMR; Q183R7; -.
DR   STRING; 272563.CD630_28300; -.
DR   MEROPS; M34.002; -.
DR   DNASU; 4913008; -.
DR   EnsemblBacteria; CAJ69718; CAJ69718; CD630_28300.
DR   GeneID; 66355238; -.
DR   KEGG; cdf:CD630_28300; -.
DR   KEGG; pdc:CDIF630_03094; -.
DR   PATRIC; fig|272563.120.peg.2981; -.
DR   eggNOG; ENOG5030AA8; Bacteria.
DR   OMA; LHEFAHS; -.
DR   BioCyc; PDIF272563:G12WB-2990-MON; -.
DR   BRENDA; 3.4.24.89; 1473.
DR   Proteomes; UP000001978; Chromosome.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   Gene3D; 3.40.390.10; -; 1.
DR   InterPro; IPR014781; Anthrax_toxin_lethal/edema_N/C.
DR   InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR   Pfam; PF07737; ATLF; 1.
DR   PROSITE; PS51995; ATLF; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Hydrolase; Metal-binding; Metalloprotease; Protease;
KW   Reference proteome; Secreted; Signal; Virulence; Zinc.
FT   SIGNAL          1..26
FT                   /evidence="ECO:0000255"
FT   CHAIN           27..220
FT                   /note="Pro-Pro endopeptidase"
FT                   /id="PRO_0000429768"
FT   DOMAIN          35..220
FT                   /note="ATLF-like"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01339"
FT   REGION          101..103
FT                   /note="Interacts with substrate peptide"
FT                   /evidence="ECO:0000269|PubMed:26211609"
FT   REGION          117..119
FT                   /note="Interacts with substrate peptide"
FT                   /evidence="ECO:0000269|PubMed:26211609"
FT   ACT_SITE        143
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01339,
FT                   ECO:0000305|PubMed:24303041, ECO:0000305|PubMed:26211609"
FT   BINDING         142
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01339,
FT                   ECO:0000269|PubMed:26211609"
FT   BINDING         146
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01339,
FT                   ECO:0000269|PubMed:26211609"
FT   BINDING         178
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01339"
FT   BINDING         185
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01339,
FT                   ECO:0000269|PubMed:26211609"
FT   SITE            135
FT                   /note="Interacts with substrate peptide"
FT                   /evidence="ECO:0000269|PubMed:26211609"
FT   SITE            142
FT                   /note="Interacts with substrate peptide"
FT                   /evidence="ECO:0000269|PubMed:26211609"
FT   SITE            178
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000305|PubMed:26211609"
FT   MUTAGEN         117..120
FT                   /note="GGST->SERV: Becomes unable to cleave VNPPVP, nor is
FT                   able to cleave PLPPVP, the optimal substrate peptide for
FT                   PPEP-2 from P.alvei."
FT                   /evidence="ECO:0000269|PubMed:29794027"
FT   MUTAGEN         143
FT                   /note="E->A: Still able to bind zinc. Highly reduced
FT                   activity on fibronectin. Loss of activity on fibrinogen.
FT                   Shows a surprising 18% residual proteolytic activity on a
FT                   substrate peptide. Total loss of proteolytic activity; when
FT                   associated with F-178."
FT                   /evidence="ECO:0000269|PubMed:24303041,
FT                   ECO:0000269|PubMed:26211609"
FT   MUTAGEN         146
FT                   /note="H->A: Not able to bind zinc. Highly reduced activity
FT                   on fibronectin. Loss of activity on fibrinogen."
FT                   /evidence="ECO:0000269|PubMed:24303041"
FT   MUTAGEN         178
FT                   /note="Y->F: Shows a surprising 41% residual proteolytic
FT                   activity on a substrate peptide. Total loss of proteolytic
FT                   activity; when associated with A-143."
FT                   /evidence="ECO:0000269|PubMed:26211609"
FT   HELIX           28..38
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   TURN            39..41
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   STRAND          46..48
FT                   /evidence="ECO:0007829|PDB:5A0R"
FT   HELIX           51..61
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           66..74
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   STRAND          79..84
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           86..88
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           90..95
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   TURN            104..107
FT                   /evidence="ECO:0007829|PDB:6R53"
FT   HELIX           110..112
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   STRAND          114..124
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   TURN            125..127
FT                   /evidence="ECO:0007829|PDB:2N6J"
FT   STRAND          132..134
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   STRAND          136..138
FT                   /evidence="ECO:0007829|PDB:5N12"
FT   HELIX           139..151
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   STRAND          153..155
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           156..158
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           160..169
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   TURN            170..173
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   TURN            176..181
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           183..196
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           198..207
FT                   /evidence="ECO:0007829|PDB:6R4Z"
FT   HELIX           209..219
FT                   /evidence="ECO:0007829|PDB:6R4Z"
SQ   SEQUENCE   220 AA;  24319 MW;  DD38BE785EFF73F4 CRC64;
     MRPSKKLLIA IISIFLISSV PVSAHADSTT IQQNKDTLSQ IVVFPTGNYD KNEANAMVNR
     LANIDGKYLN ALKQNNLKIK LLSGKLTDEK EYAYLKGVVP KGWEGTGKTW DDVPGLGGST
     VALRIGFSNK GKGHDAINLE LHETAHAIDH IVLNDISKSA QFKQIFAKEG RSLGNVNYLG
     VYPEEFFAES FAYYYLNQDT NSKLKSACPQ TYSFLQNLAK
 
 
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