WORKLIST ENTRIES (1):
NEPRILYSIN View alignment View Structure Neprilysin metalloprotease (M13) family signature
Type of fingerprint: COMPOUND with 4 elements
Links:
PRINTS; PR00756 ALADIPTASE; PR00791 PEPDIPTASEA; PR00730 THERMOLYSIN
PRINTS; PR00787 NEUTRALPTASE; PR00782 LSHMANOLYSIN; PR00997 FRAGILYSIN
PRINTS; PR00931 MICOLLPTASE; PR00765 CRBOXYPTASEA; PR00932 AMINO1PTASE
PRINTS; PR00789 OSIALOPTASE; PR00933 BLYTICPTASE; PR00934 XHISDIPTASE
PRINTS; PR00919 THERMOPTASE; PR00998 CRBOXYPTASET; PR00768 DEUTEROLYSIN
PRINTS; PR00999 FUNGALYSIN; PR01000 SREBPS2PTASE
INTERPRO; IPR000718
PROSITE; PS00142 ZINC_PROTEASE
Creation date 15-JUN-1997; UPDATE 07-JUN-1999
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).
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 FINGERPRINT INDEX
4| 29 29 29 29
3| 0 0 0 0
2| 0 0 2 2
--+---------------------
| 1 2 3 4
True positives..
ECE1_BOVIN Q28868 Q28010 ECE1_RAT
ECE1_HUMAN ECE1_CAVPO ECE2_BOVIN O60344
NEP_HUMAN NEP_MOUSE NEP_RAT O93394
NEP_RABIT O44857 Q18673 O53649
O06075 PEPO_LACLA PEPO_LACLC O35812
PEX_HUMAN PEX_MOUSE O50642 O45569
O52071 Q19831 KELL_HUMAN YCYL_CAEEL
Q22763
Subfamily: Codes involving 2 elements
Subfamily True positives..
Q25051 O45131
PROTEIN TITLES
ECE1_BOVIN ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - BOS
Q28868 ENDOTHELIN CONVERTING ENZYME - BOS TAURUS (BOVINE).
Q28010 ENDOTHELIN CONVERTING ENZYME-1A - BOS TAURUS (BOVINE).
ECE1_RAT ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - RATT
ECE1_HUMAN ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - HOMO
ECE1_CAVPO ENDOTHELIN-CONVERTING ENZYME 1 (EC 3.4.24.71) (ECE-1) - CAVI
ECE2_BOVIN ENDOTHELIN-CONVERTING ENZYME 2 (EC 3.4.24.71) (ECE-2) - BOS
O60344 KIAA0604 PROTEIN - HOMO SAPIENS (HUMAN).
NEP_HUMAN NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENK
NEP_MOUSE NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENK
NEP_RAT NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENK
O93394 NEPRILYSIN - PERCA FLAVESCENS (YELLOW PERCH).
NEP_RABIT NEPRILYSIN (EC 3.4.24.11) (NEUTRAL ENDOPEPTIDASE) (NEP) (ENK
O44857 T05A8.4 PROTEIN - CAENORHABDITIS ELEGANS.
Q18673 ZK20.6 PROTEIN - CAENORHABDITIS ELEGANS.
O53649 ZINC METALLOPROTEASE - MYCOBACTERIUM TUBERCULOSIS.
O06075 HYPOTHETICAL 75.3 KD PROTEIN - MYCOBACTERIUM LEPRAE.
PEPO_LACLA NEUTRAL ENDOPEPTIDASE (EC 3.4.24.-) (PEPTIDASE O) - LACTOCOC
PEPO_LACLC NEUTRAL ENDOPEPTIDASE (EC 3.4.24.-) (PEPTIDASE O) - LACTOCOC
O35812 PEX PROTEIN - RATTUS NORVEGICUS (RAT).
PEX_HUMAN PHOSPHATE REGULATING NEUTRAL ENDOPEPTIDASE (EC 3.4.24.-) (ME
PEX_MOUSE METALLOENDOPEPTIDASE HOMOLOG PEX (EC 3.4.24.-) (PHOSPHATE RE
O50642 PEPO - PORPHYROMONAS GINGIVALIS (BACTEROIDES GINGIVALIS).
O45569 F54F11.2 PROTEIN - CAENORHABDITIS ELEGANS.
O52071 ENDOPEPTIDASE O - LACTOBACILLUS HELVETICUS.
Q19831 SIMILAR TO NEPRILYSIN AND OTHER ZINC PROTEASES - CAENORHABDI
KELL_HUMAN KELL BLOOD GROUP GLYCOPROTEIN (EC 3.4.24.-) - HOMO SAPIENS (
YCYL_CAEEL HYPOTHETICAL ZINC METALLOPROTEINASE T16A9.4 (EC 3.4.24.-) -
Q22763 T25B6.2 PROTEIN - CAENORHABDITIS ELEGANS.
Q25051 ZINC METALLOPEPTIDASE PRECURSOR - HAEMONCHUS CONTORTUS.
O45131 PUTATIVE ZINC METALLOPEPTIDASE PRECURSOR - HAEMONCHUS CONTOR
SCAN HISTORY
OWL29_3 3 100 NSINGLE
SPTR37_9f 2 39 NSINGLE
INITIAL MOTIF SETS
NEPRILYSIN1 Length of motif = 13 Motif number = 1
Neprilysin motif I - 1
PCODE ST INT
WHMPAHMVNAYYS PEPO_LACLA 425 425
WHMPAHMVNAYYS PEPO_LACLC 425 425
WSMTPPMVNAYYS ECE1_BOVIN 542 542
WSMTPPMVNAYYS ECE1_RAT 550 550
WISGAAVVNAFYS NEP_RAT 534 534
WITGAAIVNAFYS NEP_RABIT 534 534
WKVSPWDVNAYYS KELL_HUMAN 532 532
NEPRILYSIN2 Length of motif = 13 Motif number = 2
Neprilysin motif II - 1
PCODE ST INT
IVFPAAILQAPFY PEPO_LACLA 443 5
IVFPAAILQAPFY PEPO_LACLC 443 5
IVFPAGILQAPFY ECE1_BOVIN 560 5
IVFPAGILQAPFY ECE1_RAT 568 5
IVFPAGILQPPFF NEP_RAT 552 5
IVFPAGILQPPFF NEP_RABIT 552 5
VVFPAGLLQPPFF KELL_HUMAN 550 5
NEPRILYSIN3 Length of motif = 17 Motif number = 3
Neprilysin motif III - 1
PCODE ST INT
NYGGIGAVIAHEISHAF PEPO_LACLA 464 8
NYGGIGTVIAHEISHAF PEPO_LACLC 464 8
NFGGIGVVVGHELTHAF ECE1_BOVIN 581 8
NFGGIGVVVGHELTHAF ECE1_RAT 589 8
NYGGIGMVIGHEITHGF NEP_RAT 573 8
NYGGIGMVIGHEITHGF NEP_RABIT 573 8
NFGAAGSIMAHELLHIF KELL_HUMAN 571 8
NEPRILYSIN4 Length of motif = 12 Motif number = 4
Neprilysin motif IV - 1
PCODE ST INT
ENIADQGGITAA PEPO_LACLA 534 53
ENIADQGGITAA PEPO_LACLC 534 53
ENIADNGGLKAA ECE1_BOVIN 651 53
ENIADNGGLKAA ECE1_RAT 659 53
ENIADNGGIGQA NEP_RAT 646 56
ENIADNGGIGQA NEP_RABIT 646 56
ENAADVGGLAIA KELL_HUMAN 634 46
FINAL MOTIF SETS
NEPRILYSIN1 Length of motif = 13 Motif number = 1
Neprilysin motif I - 2
PCODE ST INT
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
NEPRILYSIN2 Length of motif = 13 Motif number = 2
Neprilysin motif II - 2
PCODE ST INT
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
NEPRILYSIN3 Length of motif = 17 Motif number = 3
Neprilysin motif III - 2
PCODE ST INT
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
NEPRILYSIN4 Length of motif = 12 Motif number = 4
Neprilysin motif IV - 2
PCODE ST INT
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
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