{PDOC51885}
{PS51885; NEPRILYSIN}
{BEGIN}
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* Neprilysin-like (M13) protease domain profile *
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The neprilysin  (M13)  family  of endopeptidases are zinc-metalloenzymes [E1],
the majority of which are type II integral membrane proteins with their active
sites facing  the  extracellular  environment.  The best characterized of this
family is  neprilysin  (EC  3.4.24.11,  neural  endopeptidase, NEP), which has
important roles  in  inactivating  signaling  peptides  involved in modulating
neuronal activity,  blood pressure and the immune system. Other family members
include the  endothelin  converting  enzymes  (ECE-1  and  ECE-2),  which  are
responsible for  the  final  step  in  the synthesis of potent vasoconstrictor
endothelins, the  erythrocyte  surface  antigen KELL, the phosphate-regulating
gene on the X chromosome (PHEX), the soluble secreted endopeptidase (SEP), and
the damage-induced  neuronal  endopeptidase  (DINE)/X-converting enzyme (XCE).
Other members  of the M13 family have not been functionally characterized, but
are also   likely  to  have  biological  roles  regulating  peptide  signaling
[1,2,3,4].

The large  neprilysin-like  catalytic domain is ~675 residues in length and is
composed of  three  subdomains  (see  <PDB:3DWB>).  Two  largely alpha-helical
subdomains, which  can  be  considered as two lobes connected by intertwinning
polypeptide segments, are bridged by four intersubdomain linker segments. They
form together  a  central,  spherical  cavity  bearing  the active site of the
enzyme. The  C-terminal thermolysin-like domain includes the residues involved
in zinc  ligation and catalysis. These residues belong to the highly conserved
consensus sequences  HExxH  and  ExxxD,  and the NAY/FY motif. The zinc ion is
coordinated in  an  approximately  tetrahedral  geometry,  involving  a single
oxygen atom,  as well as three ligands from the domain, two histidine residues
from the HExxH motif and the glutamate of the ExxD motif. The glutamate of the
HExxH motif  is  directly  involved in catalysis. The second smaller subdomain
appears to  restrict  the access to the active site region and forms, together
with the  linker  fragment,  a  sieve  that  limits the size of the substrates
available to the enzyme [2,3,4].

The profile  we  developed  covers  the  entire neprilysin-like (M13) protease
domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: February 2019 / First entry.

[ 1] Bland N.D., Pinney J.W., Thomas J.E., Turner A.J., Isaac R.E.
     "Bioinformatic analysis of the neprilysin (M13) family of peptidases
     reveals complex evolutionary and functional relationships."
     BMC Evol. Biol. 8:16-16(2008).
     PubMed=18215274; DOI=10.1186/1471-2148-8-16
[ 2] Schulz H., Dale G.E., Karimi-Nejad Y., Oefner C.
     "Structure of human endothelin-converting enzyme I complexed with
     phosphoramidon."
     J. Mol. Biol. 385:178-187(2009).
     PubMed=18992253; DOI=10.1016/j.jmb.2008.10.052
[ 3] Oefner C., D'Arcy A., Hennig M., Winkler F.K., Dale G.E.
     "Structure of human neutral endopeptidase (Neprilysin) complexed with
     phosphoramidon."
     J. Mol. Biol. 296:341-349(2000).
     PubMed=10669592; DOI=10.1006/jmbi.1999.3492
[ 4] Moss S., Subramanian V., Acharya K.R.
     "High resolution crystal structure of substrate-free human
     neprilysin."
     J. Struct. Biol. 204:19-25(2018).
     PubMed=29906506; DOI=10.1016/j.jsb.2018.06.004
[E1] https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=M13

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