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PR00786

Identifier
NEPRILYSIN  [View Relations]  [View Alignment]  
Accession
PR00786
No. of Motifs
4
Creation Date
15-JUN-1997  (UPDATE 07-JUN-1999)
Title
Neprilysin metalloprotease (M13) family signature
Database References

PROSITE; PS00142 ZINC_PROTEASE
BLOCKS; BL00142
INTERPRO; IPR000718
Literature References
1. RAWLINGS, N.D. AND BARRETT, A.J.
Evolutionary families of metallopeptidases.
METHODS ENZYMOL. 248 183-228 (1995).
 
2. LE MOUAL, H., ROQUES, B.P., CRINE, P. AND BOILEAU, G.
Substitution of potential metal-coordinating amino acid residues in the 
zinc-binding site of endopeptidase-24.11.
FEBS LETT. 324 196-200 (1993).
 
3. MALFROY, B., SCHOFIELD, P.R., KUAND, W-J., SEEBURG, P.H., MASON, A.J. 
AND HENZEL, W.J.
Molecular cloning and amino acid sequence of rat enkephalinase.
BIOCHEM.BIOPHYS.RES.COMMUN. 144 59-66 (1987).

Documentation
Metalloproteases are the most diverse of the four main types of protease,
with more than 30 families identified to date [1]. Of these, around
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 
relatively common, 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 a hydrophobic residue. Proline is never found
in this site, possibly because it would break the helical structure 
adopted by this motif in metalloproteases [1].
 
Metalloproteases can be split into five groups on the basis of their metal-
binding residues: the first three contain the HEXXH motif, the other two
do not [1]. In the first group, a glutamic acid completes the active site -
these are termed HEXXH+E: all families in this group show some sequence
relationship and have been assigned to clan MA [1]. The second group, which
have a third histidine as the extra metal-binding residue, are termed
HEXXH+H and are grouped into clan MB on the basis of their inter-relation-
ship [1]. In the third group, the additional metal-binding residues are
unidentified. The fourth group is diverse - the metal-binding residues are
known but do not form the HEXXH motif. And the fifth group comprises the
remaining families where the metal-binding residues are as yet unknown [1].
 
Previously known as enkephalinase, common acute lymphocytic leukemia antigen
(CALLA) and/or neutral endopeptidase, neprilysin is a plasma membrane-bound 
mammalian enzyme that is able to digest biologically-active peptides, 
including enkephalins [1]. The family includes eukaryote and prokaryote
oligopeptidases, as well as a mammalian blood group antigen Kell [1]. The
zinc ligands of neprilysin are known and are analogous to those in 
thermolysin, a related peptidase [1,2]
 
Neprilysins, like thermolysin, are inhibited by phosphoramidon, which
appears to selectively inhibit this family in mammals. The enzymes are all
oligopeptidases, digesting oligo- and polypeptides, but not proteins [1].
Neprilysin consists of a short cytoplasmic domain, a membrane-spanning
region and a large extracellular domain. The cytoplasmic domain contains a
conformationally-restrained octapeptide, which is thought to act as a stop
transfer sequence that prevents proteolysis and secretion [1,3]
 
NEPRILYSIN is a 4-element fingerprint that provides a signature for the 
neprilysin family (M13) of metalloproteases. The fingerprint was derived
from an initial alignment of 7 sequences: the motifs were drawn from 
conserved regions within the central portion of the alignment - motif 3
includes the region encoded by PROSITE pattern ZINC_PROTEASE (PS00142),
which contains the HEXXH motif, the histidines of which are zinc ligands
and the glutamate of which is the catalytic residue; motif 4 also contains
a conserved glutamate, which provides the third zinc ligand. Three
iterations on OWL29.3 were required to reach convergence, at which point
a true set comprising 27 sequences was identified. Four partial matches
were also found, all of which are fragments.
 
An update on SPTR37_9f identified a true set of 29 sequences, and 2
partial matches.
Summary Information
  29 codes involving  4 elements
0 codes involving 3 elements
2 codes involving 2 elements
Composite Feature Index
429292929
30000
20022
1234
True Positives
ECE1_BOVIN    ECE1_CAVPO    ECE1_HUMAN    ECE1_RAT      
ECE2_BOVIN KELL_HUMAN NEP_HUMAN NEP_MOUSE
NEP_RABIT NEP_RAT O06075 O35812
O44857 O45569 O50642 O52071
O53649 O60344 O93394 PEPO_LACLA
PEPO_LACLC PEX_HUMAN PEX_MOUSE Q18673
Q19831 Q22763 Q28010 Q28868
YCYL_CAEEL
True Positive Partials
Codes involving 2 elements
O45131 Q25051
Sequence Titles
ECE1_BOVIN  ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - BOS TAURUS (BOVINE). 
ECE1_CAVPO ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - CAVIA PORCELLUS (GUINEA PIG).
ECE1_HUMAN ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - HOMO SAPIENS (HUMAN).
ECE1_RAT ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - RATTUS NORVEGICUS (RAT).
ECE2_BOVIN ENDOTHELIN-CONVERTING ENZYME 2 (EC 3.4.24.71) (ECE-2) - BOS TAURUS (BOVINE).
KELL_HUMAN KELL BLOOD GROUP GLYCOPROTEIN (EC 3.4.24.-) - HOMO SAPIENS (HUMAN).
NEP_HUMAN NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENKEPHALINASE) (COMMON ACUTE LYMPHOCYTIC LEUKEMIA ANTIGEN) (CALLA) (CD10) - HOMO SAPIENS (HUMAN).
NEP_MOUSE NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENKEPHALINASE) (CD10) - MUS MUSCULUS (MOUSE).
NEP_RABIT NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENKEPHALINASE) - ORYCTOLAGUS CUNICULUS (RABBIT).
NEP_RAT NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENKEPHALINASE) - RATTUS NORVEGICUS (RAT).
O06075 HYPOTHETICAL 75.3 KD PROTEIN - MYCOBACTERIUM LEPRAE.
O35812 PEX PROTEIN - RATTUS NORVEGICUS (RAT).
O44857 T05A8.4 PROTEIN - CAENORHABDITIS ELEGANS.
O45569 F54F11.2 PROTEIN - CAENORHABDITIS ELEGANS.
O50642 PEPO - PORPHYROMONAS GINGIVALIS (BACTEROIDES GINGIVALIS).
O52071 ENDOPEPTIDASE O - LACTOBACILLUS HELVETICUS.
O53649 ZINC METALLOPROTEASE - MYCOBACTERIUM TUBERCULOSIS.
O60344 KIAA0604 PROTEIN - HOMO SAPIENS (HUMAN).
O93394 NEPRILYSIN - PERCA FLAVESCENS (YELLOW PERCH).
PEPO_LACLA NEUTRAL ENDOPEPTIDASE (EC 3.4.24.-) (PEPTIDASE O) - LACTOCOCCUS LACTIS (SUBSP. LACTIS) (STREPTOCOCCUS LACTIS).
PEPO_LACLC NEUTRAL ENDOPEPTIDASE (EC 3.4.24.-) (PEPTIDASE O) - LACTOCOCCUS LACTIS (SUBSP. CREMORIS) (STREPTOCOCCUS CREMORIS).
PEX_HUMAN PHOSPHATE REGULATING NEUTRAL ENDOPEPTIDASE (EC 3.4.24.-) (METALLOENDOPEPTIDASE HOMOLOG PEX) (X-LINKED HYPOPHOSPHATEMIA PROTEIN) (HYP) (VITAMIN D-RESISTANT HYPOPHOSPHATEMIC RICKETS PROTEIN) - HOMO SAPIENS (HUMAN).
PEX_MOUSE METALLOENDOPEPTIDASE HOMOLOG PEX (EC 3.4.24.-) (PHOSPHATE REGULATING NEUTRAL ENDOPEPTIDASE) (X-LINKED HYPOPHOSPHATEMIA PROTEIN) (HYP) (VITAMIN D-RESISTANT HYPOPHOSPHATEMIC RICKETS PROTEIN) - MUS MUSCULUS (MOUSE).
Q18673 ZK20.6 PROTEIN - CAENORHABDITIS ELEGANS.
Q19831 SIMILAR TO NEPRILYSIN AND OTHER ZINC PROTEASES - CAENORHABDITIS ELEGANS.
Q22763 T25B6.2 PROTEIN - CAENORHABDITIS ELEGANS.
Q28010 ENDOTHELIN CONVERTING ENZYME-1A - BOS TAURUS (BOVINE).
Q28868 ENDOTHELIN CONVERTING ENZYME - BOS TAURUS (BOVINE).
YCYL_CAEEL HYPOTHETICAL ZINC METALLOPROTEINASE T16A9.4 (EC 3.4.24.-) - CAENORHABDITIS ELEGANS.

O45131 PUTATIVE ZINC METALLOPEPTIDASE PRECURSOR - HAEMONCHUS CONTORTUS.
Q25051 ZINC METALLOPEPTIDASE PRECURSOR - HAEMONCHUS CONTORTUS.
Scan History
OWL29_3    3  100  NSINGLE    
SPTR37_9f 2 39 NSINGLE
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
WSMTPPMVNAYYS ECE1_BOVIN 542 542 -
WSMTPPMVNAYYS ECE1_RAT 550 550 -
WISGAAVVNAFYS NEP_RAT 534 534 -
WITGAAIVNAFYS NEP_RABIT 534 534 -
WHMPAHMVNAYYS PEPO_LACLA 425 425 -
WHMPAHMVNAYYS PEPO_LACLC 425 425 -
WKVSPWDVNAYYS KELL_HUMAN 532 532 -

Motif 2 width=13
Element Seqn Id St Int Rpt
IVFPAGILQAPFY ECE1_BOVIN 560 5 -
IVFPAGILQAPFY ECE1_RAT 568 5 -
IVFPAGILQPPFF NEP_RAT 552 5 -
IVFPAGILQPPFF NEP_RABIT 552 5 -
IVFPAAILQAPFY PEPO_LACLA 443 5 -
IVFPAAILQAPFY PEPO_LACLC 443 5 -
VVFPAGLLQPPFF KELL_HUMAN 550 5 -

Motif 3 width=17
Element Seqn Id St Int Rpt
NFGGIGVVVGHELTHAF ECE1_BOVIN 581 8 -
NFGGIGVVVGHELTHAF ECE1_RAT 589 8 -
NYGGIGMVIGHEITHGF NEP_RAT 573 8 -
NYGGIGMVIGHEITHGF NEP_RABIT 573 8 -
NYGGIGAVIAHEISHAF PEPO_LACLA 464 8 -
NYGGIGTVIAHEISHAF PEPO_LACLC 464 8 -
NFGAAGSIMAHELLHIF KELL_HUMAN 571 8 -

Motif 4 width=12
Element Seqn Id St Int Rpt
ENIADNGGLKAA ECE1_BOVIN 651 53 -
ENIADNGGLKAA ECE1_RAT 659 53 -
ENIADNGGIGQA NEP_RAT 646 56 -
ENIADNGGIGQA NEP_RABIT 646 56 -
ENIADQGGITAA PEPO_LACLA 534 53 -
ENIADQGGITAA PEPO_LACLC 534 53 -
ENAADVGGLAIA KELL_HUMAN 634 46 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
WSMTPPMVNAYYS ECE1_BOVIN 542 542 -
WSMTPPMVNAYYS Q28868 546 546 -
WSMTPPMVNAYYS Q28010 546 546 -
WSMTPPMVNAYYS ECE1_RAT 550 550 -
WSMTPPMVNAYYS ECE1_HUMAN 558 558 -
WSMTPPMVNAYYS ECE1_CAVPO 542 542 -
WSMTPQTVNAYYL ECE2_BOVIN 575 575 -
WSMTPQTVNAYYL O60344 553 553 -
WISGAAVVNAFYS NEP_HUMAN 534 534 -
WISGAAVVNAFYS NEP_MOUSE 534 534 -
WISGAAVVNAFYS NEP_RAT 534 534 -
WVTGAAVVNAFYS O93394 555 555 -
WITGAAIVNAFYS NEP_RABIT 534 534 -
WVAGAALVNAFYS O44857 522 522 -
FISSAAVVNAFYS Q18673 550 550 -
WFMTPQTVNAYYN O06075 452 452 -
WFMTPQTVNAYYN O53649 444 444 -
WHMPAHMVNAYYS PEPO_LACLA 425 425 -
WHMPAHMVNAYYS PEPO_LACLC 425 425 -
WFTNPTTVNAFYS O35812 530 530 -
WFTNPTTVNAFYS PEX_HUMAN 530 530 -
WFTNPTTVNAFYS PEX_MOUSE 530 530 -
WLMNPQDVNAYYN O50642 477 477 -
GITPRALVNYFYY O45569 412 412 -
WLMPGNLNNACYD O52071 447 447 -
WASPIIAVDAFHY Q19831 539 539 -
WKVSPWDVNAYYS KELL_HUMAN 532 532 -
WFQSPAQVDAYYA YCYL_CAEEL 552 552 -
FLQSPAMVNAWYQ Q22763 565 565 -

Motif 2 width=13
Element Seqn Id St Int Rpt
IVFPAGILQAPFY ECE1_BOVIN 560 5 -
IVFPAGILQAPFY Q28868 564 5 -
IVFPAGILQAPFY Q28010 564 5 -
IVFPAGILQAPFY ECE1_RAT 568 5 -
IVFPAGILQAPFY ECE1_HUMAN 576 5 -
IVFPAGILPAPFY ECE1_CAVPO 560 5 -
IVFPAGILQAPFY ECE2_BOVIN 593 5 -
IVFPAGILQAPFY O60344 571 5 -
IVFPAGILQPPFF NEP_HUMAN 552 5 -
IVFPAGILQPPFF NEP_MOUSE 552 5 -
IVFPAGILQPPFF NEP_RAT 552 5 -
IVFPAGILQPPFF O93394 573 5 -
IVFPAGILQPPFF NEP_RABIT 552 5 -
SVFPAGILQPVFY O44857 554 19 -
IAFPAGILQQPFF Q18673 568 5 -
IVFPAAILQPPFF O06075 470 5 -
IVFPAAILQPPFF O53649 462 5 -
IVFPAAILQAPFY PEPO_LACLA 443 5 -
IVFPAAILQAPFY PEPO_LACLC 443 5 -
IRFPAGELQKPFF O35812 548 5 -
IRFPAGELQKPFF PEX_HUMAN 548 5 -
IRFPAGELQKPFF PEX_MOUSE 548 5 -
ICFPAAILQPPFF O50642 495 5 -
ITFPAGILKKPFY O45569 629 204 -
LTFPAGILQAPFY O52071 465 5 -
IIFPAGILQFPMF Q19831 557 5 -
VVFPAGLLQPPFF KELL_HUMAN 550 5 -
MIFPAGIMQFPFL YCYL_CAEEL 570 5 -
ITFPYAAWNPPYY Q22763 583 5 -

Motif 3 width=17
Element Seqn Id St Int Rpt
NFGGIGVVVGHELTHAF ECE1_BOVIN 581 8 -
NFGGIGVVVGHELTHAF Q28868 585 8 -
NFGGIGVVVGHELTHAF Q28010 585 8 -
NFGGIGVVVGHELTHAF ECE1_RAT 589 8 -
NFGGIGVVVGHELTHAF ECE1_HUMAN 597 8 -
NFGGIGVVVGHELTHAF ECE1_CAVPO 581 8 -
NFGGIGVVMGHELTHAF ECE2_BOVIN 614 8 -
NFGGIGVVMGHELTHAF O60344 592 8 -
NYGGIGMVIGHEITHGF NEP_HUMAN 573 8 -
NYGGIGMVIGHEITHGF NEP_MOUSE 573 8 -
NYGGIGMVIGHEITHGF NEP_RAT 573 8 -
NYGGIGMVIGHEITHGF O93394 594 8 -
NYGGIGMVIGHEITHGF NEP_RABIT 573 8 -
NFGGIGVVIGHEITHGF O44857 575 8 -
NYGGIGAVIGHEITHGF Q18673 589 8 -
NYGGIGAVIGHEIGHGF O06075 491 8 -
NYGGIGAVIGHEIGHGF O53649 483 8 -
NYGGIGAVIAHEISHAF PEPO_LACLA 464 8 -
NYGGIGTVIAHEISHAF PEPO_LACLC 464 8 -
SYGAIGVIVGHEFTHGF O35812 570 9 -
SYGAIGVIVGHEFTHGF PEX_HUMAN 570 9 -
SYGAIGVIVGHEFTHGF PEX_MOUSE 570 9 -
NYGGIGVVIGHEMTHGF O50642 516 8 -
NYGGMGLVAGHELTHGF O45569 1400 758 -
NYGGIGATIGHEVSHAF O52071 486 8 -
NYGAIGMGIGHEITHGY Q19831 578 8 -
NFGAAGSIMAHELLHIF KELL_HUMAN 571 8 -
TYGMVGAVIGHEVSHAF YCYL_CAEEL 591 8 -
NFAGQGGTGGHELTHGY Q22763 604 8 -

Motif 4 width=12
Element Seqn Id St Int Rpt
ENIADNGGLKAA ECE1_BOVIN 651 53 -
ENIADNGGLKAA Q28868 655 53 -
ENIADNGGLKAA Q28010 655 53 -
ENIADNGGLKAA ECE1_RAT 659 53 -
ENIADNGGLKAA ECE1_HUMAN 667 53 -
ENIADNGGLKAA ECE1_CAVPO 651 53 -
ENIADNGGLKAA ECE2_BOVIN 684 53 -
ENIADNGGLKAA O60344 662 53 -
ENIADNGGLGQA NEP_HUMAN 646 56 -
ENIADNGGIGQA NEP_MOUSE 646 56 -
ENIADNGGIGQA NEP_RAT 646 56 -
ENIADNGGIRQA O93394 667 56 -
ENIADNGGIGQA NEP_RABIT 646 56 -
ENIADNGGLKQA O44857 647 55 -
ENIADNGGIKQA Q18673 661 55 -
ENIGDLGGLSIA O06075 564 56 -
ENIGDLGGLSIA O53649 560 60 -
ENIADQGGITAA PEPO_LACLA 534 53 -
ENIADQGGITAA PEPO_LACLC 534 53 -
ENIADNGGLREA O35812 642 55 -
ENIADNGGLREA PEX_HUMAN 642 55 -
ENIADNGGLREA PEX_MOUSE 642 55 -
ENIADQGGLLIS O50642 587 54 -
ENIADNGGVHAA O45569 1476 59 -
ENIADLAGLACA O52071 556 53 -
ENIADNGGLRVA Q19831 650 55 -
ENAADVGGLAIA KELL_HUMAN 634 46 -
ENIADNGGVKTA YCYL_CAEEL 663 55 -
ENIADLGGQQAA Q22763 686 65 -