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PR00730

Identifier
THERMOLYSIN  [View Relations]  [View Alignment]  
Accession
PR00730
No. of Motifs
4
Creation Date
10-FEB-1997  (UPDATE 10-JUN-1999)
Title
Thermolysin metalloprotease (M4) family signature
Database References

PROSITE; PS00142 ZINC_PROTEASE
BLOCKS; BL00142
INTERPRO; IPR001570
PDB; 1TMN
SCOP; 1TMN
CATH; 1TMN
Literature References
1. RAWLINGS, N.D. AND BARRETT, A.J.
Evolutionary families of metallopeptidases.
METHODS ENZYMOL. 248 183-228 (1995).

Documentation
Metalloproteases are the most diverse of the four main types of protease,
with more than 30 families identified to date [1]. Of these, approximately
half contain the HEXXH motif, which has been shown in crystallographic
studies to form part of the metal-binding site [1]. The HEXXH motif is 
quite common in proteins, but can be more stringently defined for metallo-
proteases as abXHEbbHbc, where a is most often valine or threonine and 
forms part of the S1' subsite in thermolysin and neprilysin, b is an
uncharged residue, and c is a hydrophobic residue. Proline is never found
in this site, possibly because it would break the helical structure the
motif has been shown to form in metalloproteases [1].
 
Metalloproteases can be split into five groups on the basis of the metal-
binding residues: the first three contain the HEXXH motif, the other two
do not [1]. The first group contain an additional glutamic acid, which
completes the active site and are termed HEXXH+E: all families in this
group show some sequence similarity and have thus been grouped into clan
MA [1]. In the second group, a third histidine constitutes the extra metal-
binding residue: these are termed HEXXH+H and are grouped into clan MB [1].
The additional metal-binding residues in the third group are unidentified.
In the fourth group, the metal-binding residues are known, but in the fifth
group these residues are as yet unknown [1].
 
The thermolysin family (M4), part of the MA clan (HEXXH+E), is composed 
only of secreted eubacterial endopeptidases [1]. The zinc-binding residues
are H-142, H-146 and E-166, with E-143 acting as the catalytic residue [1].
Thermolysin also contains 4 calcium-binding sites, which contribute to its
unusual thermostability [1]. The family also includes enzymes from a number
of pathogens, including Legionella and Listeria, and the protein pseudolysin,
all with a substrate specificity for an aromatic residue in the P1' position
[1]. Three-dimensional structure analysis has shown that the enzymes undergo 
a hinge-bend motion during catalysis [1]. Pseudolysin has a broader
specificity, acting on large molecules such as elastin and collagen,
possibly due to its wider active site cleft [1].
 
THERMOLYSIN is a 4-element fingerprint that provides a signature for the
thermolysin metalloprotease (M4) family. The fingerprint was derived from 
an initial alignment of 5 sequences: the motifs were drawn from conserved
regions surrounding the active site - motif 2 includes the region encoded
by PROSITE pattern ZINC_PROTEASE (PS00142), which contains the HEXXH motif,
the His residues of which provide the zinc ligands, the Glu being the
active site residue; and motif 3 contains the additional metal-binding
residue (E-166). Three iterations on OWL29.1 were required to reach
convergence, at which point a true set comprising 34 sequences was
identified. Two partial matches were also found: A38166 is a probable
elastase precursor that lacks a match with motif 4; and SMP_SERMA is an
extracellular minor metalloprotease precursor, a member of the M4 family,
that lacks a match with motif 1.
 
An update on SPTR37_9f identified a true set of 34 sequences, and 1
partial match.
Summary Information
  34 codes involving  4 elements
1 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
434343434
30111
20000
1234
True Positives
AURE_STAAU    ELAS_PSEAE    EMPA_VIBAN    HAPT_VIBCH    
NPRB_BACSU NPRE_BACAM NPRE_BACBR NPRE_BACCE
NPRE_BACCL NPRE_BACSU NPRE_PAEPO NPRM_BACME
NPRS_BACST NPRV_VIBPR O06694 O32309
P96176 PRO1_LISMO PRO2_LISMO PROA_LEGLO
PROA_LEGPN PRT1_ERWCA PRZN_RENSA Q43880
Q44677 Q45779 Q46237 Q47786
Q48857 Q59193 Q59223 SEPA_STAEP
THER_BACST THER_BACTH
True Positive Partials
Codes involving 3 elements
SMP_SERMA
Sequence Titles
AURE_STAAU  ZINC METALLOPROTEINASE AUREOLYSIN (EC 3.4.24.29) (STAPHYLOCOCCUS AUREUS NEUTRAL PROTEINASE) - STAPHYLOCOCCUS AUREUS. 
ELAS_PSEAE PSEUDOLYSIN PRECURSOR (EC 3.4.24.26) (ELASTASE) (NEUTRAL METALLOPROTEINASE) - PSEUDOMONAS AERUGINOSA.
EMPA_VIBAN VIRULENCE METALLOPROTEASE PRECURSOR (EC 3.4.24.-) (VIBRIOLYSIN) - VIBRIO ANGUILLARUM.
HAPT_VIBCH HEMAGGLUTININ/PROTEINASE PRECURSOR (EC 3.4.24.-) (HA/PROTEASE) (VIBRIOLYSIN) - VIBRIO CHOLERAE.
NPRB_BACSU NEUTRAL PROTEASE B PRECURSOR (EC 3.4.24.-) - BACILLUS SUBTILIS.
NPRE_BACAM BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) - BACILLUS AMYLOLIQUEFACIENS.
NPRE_BACBR BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) - BACILLUS BREVIS.
NPRE_BACCE BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) - BACILLUS CEREUS.
NPRE_BACCL BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (THERMOSTABLE NEUTRAL PROTEASE) - BACILLUS CALDOLYTICUS.
NPRE_BACSU BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) (MCP 76) - BACILLUS SUBTILIS, BACILLUS SUBTILIS VAR. AMYLOSACCHARITICUS, AND BACILLUS MESENTERICUS.
NPRE_PAEPO BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) - PAENIBACILLUS POLYMYXA (BACILLUS POLYMYXA).
NPRM_BACME BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) - BACILLUS MEGATERIUM.
NPRS_BACST BACILLOLYSIN PRECURSOR (EC 3.4.24.28) (NEUTRAL PROTEASE) - BACILLUS STEAROTHERMOPHILUS.
NPRV_VIBPR NEUTRAL PROTEASE PRECURSOR (EC 3.4.24.25) (VIBRIOLYSIN) (AEROMONOLYSIN) - VIBRIO PROTEOLYTICUS (AEROMONAS PROTEOLYTICA).
O06694 METALLOPROTEASE - VIBRIO VULNIFICUS.
O32309 NEUTRAL PROTEASE A - BACILLUS THURINGIENSIS.
P96176 NEUTRAL PROTEASE PRECURSOR (EC 3.4.24.-) (VIBRIOLYSIN) - VIBRIO VULNIFICUS.
PRO1_LISMO ZINC METALLOPROTEINASE PRECURSOR (EC 3.4.24.-) - LISTERIA MONOCYTOGENES.
PRO2_LISMO ZINC METALLOPROTEINASE PRECURSOR (EC 3.4.24.-) - LISTERIA MONOCYTOGENES.
PROA_LEGLO ZINC METALLOPROTEINASE PRECURSOR (EC 3.4.24.-) - LEGIONELLA LONGBEACHAE.
PROA_LEGPN ZINC METALLOPROTEINASE PRECURSOR (EC 3.4.24.-) (PEP1) (PRO A) - LEGIONELLA PNEUMOPHILA.
PRT1_ERWCA EXTRACELLULAR METALLOPROTEASE PRECURSOR (EC 3.4.24.-) - ERWINIA CAROTOVORA.
PRZN_RENSA ZINC METALLOPROTEINASE PRECURSOR (EC 3.4.24.-) (HEMOLYSIN) - RENIBACTERIUM SALMONINARUM.
Q43880 THERMOLYSIN PRECURSOR (EC 3.4.24.27) (THERMOSTABLE NEUTRAL PROTEINASE) - ALICYCLOBACILLUS ACIDOCALDARIUS (BACILLUS ACIDOCALDARIUS).
Q44677 NEUTRAL PROTEASE - BACILLUS AMYLOLIQUEFACIENS.
Q45779 THERMOLYSIN - BACILLUS THERMOPROTEOLYTICUS.
Q46237 LAMBDA TOXIN - CLOSTRIDIUM PERFRINGENS.
Q47786 GELATINASE - ENTEROCOCCUS FAECALIS (STREPTOCOCCUS FAECALIS).
Q48857 HYDROLASE PRECURSOR - LACTOBACILLUS SP.
Q59193 THERMOLYSIN PRECURSOR (EC 3.4.24.27) (THERMOSTABLE NEUTRAL PROTEINASE) - BACILLUS CALDOLYTICUS.
Q59223 THERMOLYSIN PRECURSOR (EC 3.4.24.27) (THERMOSTABLE NEUTRAL PROTEINASE) - BACILLUS SP.
SEPA_STAEP EXTRACELLULAR ELASTASE PRECURSOR (EC 3.4.24.-) (SEPP1) - STAPHYLOCOCCUS EPIDERMIDIS.
THER_BACST THERMOLYSIN PRECURSOR (EC 3.4.24.27) (THERMOSTABLE NEUTRAL PROTEINASE) - BACILLUS STEAROTHERMOPHILUS.
THER_BACTH THERMOLYSIN (EC 3.4.24.27) - BACILLUS THERMOPROTEOLYTICUS.

SMP_SERMA EXTRACELLULAR MINOR METALLOPROTEASE PRECURSOR (EC 3.4.24.-) - SERRATIA MARCESCENS.
Scan History
OWL29_1    3  100  NSINGLE    
SPTR37_9f 2 36 NSINGLE
Initial Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
HVGKQWNNAAWNGVQMVYGDG NPRB_BACSU 332 332 -
HYGLNCNNAFWDGQEILYGDG PRO1_LISMO 312 312 -
HYDSNYENAFWNGSSMTFGDG EMPA_VIBAN 311 311 -
HYGNNYENAFWDGRAMTFGDG HAPT_VIBCH 308 308 -
HYGRSVENAYWDGTAMLFGDG ELAS_PSEAE 302 302 -

Motif 2 width=17
Element Seqn Id St Int Rpt
AHEITHAVTQYSAGLLY NPRB_BACSU 368 15 -
GHELTHAVIQYSAGLEY PRO1_LISMO 348 15 -
AHEVSHGFTEQNSGLVY EMPA_VIBAN 345 13 -
AHEVSHGFTEQNSGLVY HAPT_VIBCH 342 13 -
AHEVSHGFTEQNSGLIY ELAS_PSEAE 336 13 -

Motif 3 width=12
Element Seqn Id St Int Rpt
GALNESISDIMG NPRB_BACSU 389 4 -
GALNESFADVFG PRO1_LISMO 369 4 -
GGINEAFSDIAG EMPA_VIBAN 366 4 -
GGINEAFSDIAG HAPT_VIBCH 363 4 -
GGMNEAFSDMAG ELAS_PSEAE 357 4 -

Motif 4 width=17
Element Seqn Id St Int Rpt
VHINSSIHNKAAYLLAE NPRB_BACSU 452 51 -
VHYNSGIPNKAAYNTIT PRO1_LISMO 436 55 -
VHYSSGVFNRAYYLLAN EMPA_VIBAN 428 50 -
VHHSSGVFNRAFYLLAN HAPT_VIBCH 425 50 -
VHHSSGVYNRAFYLLAN ELAS_PSEAE 419 50 -
Final Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
HYGRGYNNAFWNGSQMVYGDG NPRE_BACCL 333 333 -
HYGRGYNNAFWNGSQMVYGDG THER_BACST 337 337 -
HYGRGYNNAFWNGSQMVYGDG Q59223 335 335 -
HYGRGYNNAFWNGSQMVYGDG Q59193 335 335 -
HYGRGYNNAFWNGSQMVYGDG Q43880 335 335 -
HYGSKYNNAFWNGSQMVYGDG Q48857 355 355 -
HYSTRYNNAFWNGSQMVYGDG NPRE_BACBR 321 321 -
HYGSNYNNAFWNGSQMVYGDG NPRE_BACCE 355 355 -
HYGSNYNNAFWNGSQMVYGDG O32309 355 355 -
HYSQGYNNAFWNGSQMVYGDG NPRS_BACST 340 340 -
HYSQGYNNAFWNGSQMVYGDG Q45779 337 337 -
HYSSGYNNAFWNGSQMVYGDG NPRM_BACME 351 351 -
HYGSRYNNAFWNGSQMTYGDG NPRE_PAEPO 384 384 -
HYSQGYNNAFWNGSEMVYGDG THER_BACTH 105 105 -
HYGSRYNNAAWIGDQMIYGDG NPRE_BACAM 327 327 -
HYGTQYNNAAWTGDQMIYGDG NPRE_BACSU 327 327 -
QYGSRYNNAAWIGDQMIYGDG Q44677 327 327 -
HYGQDYQNAFWNGQQMVFGDG PRT1_ERWCA 125 125 -
HYGSNYNNAYWNGYKMIYGDG Q46237 337 337 -
HVGKQWNNAAWNGVQMVYGDG NPRB_BACSU 332 332 -
GGQDNRNNAAWIGDKMIYGDG AURE_STAAU 107 107 -
QGQDNRNNAAWIGDKMIYGDG SEPA_STAEP 314 314 -
HYGNNYENAFWNGSSMTFGDG NPRV_VIBPR 308 308 -
HYGLNCNNAFWDGQEILYGDG PRO1_LISMO 312 312 -
HYGLNCNNAFWDGREILYGDG PRO2_LISMO 312 312 -
HYDSNYENAFWNGSSMTFGDG EMPA_VIBAN 311 311 -
HYSSNYENAFWDGSAMTFGDG O06694 308 308 -
HYSSNYENAFWDGSAMTFGDG P96176 308 308 -
HYGNNYENAFWDGRAMTFGDG HAPT_VIBCH 308 308 -
HYGRSVENAYWDGTAMLFGDG ELAS_PSEAE 302 302 -
GEQCPFANAFWYNGQMTYGQG PRZN_RENSA 333 333 -
HYGQGYENAYWDGKQMTFGDG PROA_LEGPN 342 342 -
QHPDAYDNAFWDGKAMRYGET Q47786 290 290 -
HYGDGYENAYWDGEQMTFGCG PROA_LEGLO 330 330 -

Motif 2 width=17
Element Seqn Id St Int Rpt
GHELTHAVTDYTAGLVY NPRE_BACCL 369 15 -
GHELTHAVTDYTAGLVY THER_BACST 373 15 -
GHELTHAVTDYTAGLVY Q59223 371 15 -
GHELTHAVTDYTAGLVY Q59193 371 15 -
GHELTHAVTDYTAGLVY Q43880 371 15 -
GHELTHAVTEYSSDLIY Q48857 391 15 -
AHELTHAVTERTAGLVY NPRE_BACBR 357 15 -
GHELTHAVTENSSNLIY NPRE_BACCE 391 15 -
GHELTHAVTENSSNLIY O32309 391 15 -
AHELTHAVTDYTAGLIY NPRS_BACST 376 15 -
AHELTHAVTDYTAGLIY Q45779 373 15 -
GHELTHALTERSSNLIY NPRM_BACME 387 15 -
GHELTHGVTEYTSNLEY NPRE_PAEPO 422 17 -
AHELTHAVTDYTAGLIY THER_BACTH 141 15 -
AHEMTHGVTQETANLNY NPRE_BACAM 363 15 -
AHEMTHGVTQETANLIY NPRE_BACSU 363 15 -
AHEMTHGVTQETANLNY Q44677 363 15 -
AHELTHGITENEAGLIY PRT1_ERWCA 161 15 -
GHEMTHGVVTNTCNLNY Q46237 373 15 -
AHEITHAVTQYSAGLLY NPRB_BACSU 368 15 -
AHEITHGVTQQTANLEY AURE_STAAU 143 15 -
AHEITHGVTQQTANLVY SEPA_STAEP 350 15 -
AHEVSHGFTEQNSGLVY NPRV_VIBPR 342 13 -
GHELTHAVIQYSAGLEY PRO1_LISMO 348 15 -
GHELTHAVIQYSAGLEY PRO2_LISMO 348 15 -
AHEVSHGFTEQNSGLVY EMPA_VIBAN 345 13 -
AHEVSHGFTEQNSGLIY O06694 342 13 -
AHEVSHGFTEQNSGLIY P96176 342 13 -
AHEVSHGFTEQNSGLVY HAPT_VIBCH 342 13 -
AHEVSHGFTEQNSGLIY ELAS_PSEAE 336 13 -
GHELTHGVTEKTNGLVY PRZN_RENSA 361 7 -
GHEVSHGFTEQHSGLEY PROA_LEGPN 376 13 -
GHEMTHGVTEHTAGLEY Q47786 326 15 -
AHEISHGFTEQHSGLEY PROA_LEGLO 364 13 -

Motif 3 width=12
Element Seqn Id St Int Rpt
GAINEAMSDIFG NPRE_BACCL 390 4 -
GAINEAMSDIFG THER_BACST 394 4 -
GAINEAMSDIFG Q59223 392 4 -
GAINEAMSDIFG Q59193 392 4 -
GAINEAMSDIFG Q43880 392 4 -
GALNEAISDVFG Q48857 412 4 -
GALNESMSDIFG NPRE_BACBR 378 4 -
GALNEAISDIFG NPRE_BACCE 412 4 -
GALNEAISDIFG O32309 412 4 -
GAINEAISDIFG NPRS_BACST 397 4 -
GAINEAMSDIFG Q45779 394 4 -
GALNEAISDIFG NPRM_BACME 408 4 -
GALNEAFSDVIG NPRE_PAEPO 443 4 -
GAINEAISDIFG THER_BACTH 162 4 -
GALNESFSDVFG NPRE_BACAM 384 4 -
GALNESFSDVFG NPRE_BACSU 384 4 -
GALNESFSDVFG Q44677 384 4 -
GALNESLSDVFG PRT1_ERWCA 182 4 -
GALNESISDVFG Q46237 394 4 -
GALNESISDIMG NPRB_BACSU 389 4 -
GALNESFSDVFG AURE_STAAU 164 4 -
GALNESFSDVFG SEPA_STAEP 371 4 -
GGMNEAFSDIAG NPRV_VIBPR 363 4 -
GALNESFADVFG PRO1_LISMO 369 4 -
GALNESFADVFG PRO2_LISMO 369 4 -
GGINEAFSDIAG EMPA_VIBAN 366 4 -
GGMNEAFSDIAG O06694 363 4 -
GGMNEAFSDIAG P96176 363 4 -
GGINEAFSDIAG HAPT_VIBCH 363 4 -
GGMNEAFSDMAG ELAS_PSEAE 357 4 -
GAINESMSDVFG PRZN_RENSA 382 4 -
GGMNESFSDMAA PROA_LEGPN 397 4 -
GALNESYSDLMG Q47786 347 4 -
GGMNESFSDMAA PROA_LEGLO 385 4 -

Motif 4 width=17
Element Seqn Id St Int Rpt
VHTNSGIINKAAYLLSQ NPRE_BACCL 458 56 -
VHTNSGIINKAAYLLSQ THER_BACST 462 56 -
VHTNSGIINKAAYLLSQ Q59223 460 56 -
VHTNSGIINKAAYLLSQ Q59193 460 56 -
VHTNSGIINKAAYLLSQ Q43880 460 56 -
VHTNSGIINKAAYLLAN Q48857 480 56 -
VHTNSGINNKAAYLLAE NPRE_BACBR 441 51 -
VHTNSGIINKQAYLLAN NPRE_BACCE 480 56 -
VHTNSGIINKQAYLLAN O32309 480 56 -
VHINSGIINKAAYLISQ NPRS_BACST 465 56 -
VHINSGIINKAAYLISQ Q45779 462 56 -
VHTNSGIINKAAYLLAN NPRM_BACME 476 56 -
VHTNSGIINKAYYLLAQ NPRE_PAEPO 506 51 -
VHINSGIINKAAYLISQ THER_BACTH 230 56 -
VHTNSGIPNKAAYNTIT NPRE_BACAM 448 52 -
VHTNSGIPNKAAYNTIT NPRE_BACSU 448 52 -
VHTNSGIPNKAAYNTIT Q44677 448 52 -
VHLNSGIPNRAFYLAAI PRT1_ERWCA 263 69 -
VHINSGIPNKAAYNLAS Q46237 477 71 -
VHINSSIHNKAAYLLAE NPRB_BACSU 452 51 -
VHTNSGIPNKAAYNVIQ AURE_STAAU 227 51 -
VHTNSGIPNKAAYNTIR SEPA_STAEP 434 51 -
VHYSSGVFNRAFYLLAN NPRV_VIBPR 425 50 -
VHYNSGIPNKAAYNTIT PRO1_LISMO 436 55 -
VHFNSGIPNKAAYNTIT PRO2_LISMO 436 55 -
VHYSSGVFNRAYYLLAN EMPA_VIBAN 428 50 -
VHHSSGVYNRAFYLLAN O06694 425 50 -
VHHSSGVYNRAFYLLAN P96176 425 50 -
VHHSSGVFNRAFYLLAN HAPT_VIBCH 425 50 -
VHHSSGVYNRAFYLLAN ELAS_PSEAE 419 50 -
VHSNSGVGNKLAFLITD PRZN_RENSA 458 64 -
VHYSSGVYNHLFYILAN PROA_LEGPN 462 53 -
VHYNSGIINRIGYTIIQ Q47786 417 58 -
VHYSSGVYNHLFYILAT PROA_LEGLO 450 53 -