|PROSITE documentation PDOC51885|
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 22.214.171.124, 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 α-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.Last update:
February 2019 / First entry.
PROSITE method (with tools and information) covered by this documentation:
|1||Authors||Bland N.D. Pinney J.W. Thomas J.E. Turner A.J. Isaac R.E.|
|Title||Bioinformatic analysis of the neprilysin (M13) family of peptidases reveals complex evolutionary and functional relationships.|
|Source||BMC Evol. Biol. 8:16-16(2008).|
|2||Authors||Schulz H. Dale G.E. Karimi-Nejad Y. Oefner C.|
|Title||Structure of human endothelin-converting enzyme I complexed with phosphoramidon.|
|Source||J. Mol. Biol. 385:178-187(2009).|
|3||Authors||Oefner C. D'Arcy A. Hennig M. Winkler F.K. Dale G.E.|
|Title||Structure of human neutral endopeptidase (Neprilysin) complexed with phosphoramidon.|
|Source||J. Mol. Biol. 296:341-349(2000).|
|4||Authors||Moss S. Subramanian V. Acharya K.R.|
|Title||High resolution crystal structure of substrate-free human neprilysin.|
|Source||J. Struct. Biol. 204:19-25(2018).|