Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Crystal structure of the human carboxypeptidase N (kininase I) catalytic domain

Keil, Cora, Maskos, Klaus, Than, Manuel, Hoopes, J. Todd, Huber, Robert, Tan, Fulong, Deddish, Peter A., Erdös, Ervin G., Skidgel, Randal A. and Bode, Wolfram 2007. Crystal structure of the human carboxypeptidase N (kininase I) catalytic domain. Journal of Molecular Biology 366 (2) , pp. 504-516. 10.1016/j.jmb.2006.11.025

Full text not available from this repository.

Abstract

Human carboxypeptidase N (CPN), a member of the CPN/E subfamily of “regulatory” metallo-carboxypeptidases, is an extracellular glycoprotein synthesized in the liver and secreted into the blood, where it controls the activity of vasoactive peptide hormones, growth factors and cytokines by specifically removing C-terminal basic residues. Normally, CPN circulates in blood plasma as a hetero-tetramer consisting of two 83 kDa (CPN2) domains each flanked by a 48 to 55 kDa catalytic (CPN1) domain. We have prepared and crystallized the recombinant C-terminally truncated catalytic domain of human CPN1, and have determined and refined its 2.1 Å crystal structure. The structural analysis reveals that CPN1 has a pear-like shape, consisting of a 319 residue N-terminal catalytic domain and an abutting, cylindrically shaped 79 residue C-terminal β-sandwich transthyretin (TT) domain, more resembling CPD-2 than CPM. Like these other CPN/E members, two surface loops surrounding the active-site groove restrict access to the catalytic center, offering an explanation for why some larger protein carboxypeptidase inhibitors do not inhibit CPN. Modeling of the Pro-Phe-Arg C-terminal end of the natural substrate bradykinin into the active site shows that the S1′ pocket of CPN1 might better accommodate P1′-Lys than Arg residues, in agreement with CPN's preference for cleaving off C-terminal Lys residues. Three Thr residues at the distal TT edge of CPN1 are O-linked to N-acetyl glucosamine sugars; equivalent sites in the membrane-anchored CPM are occupied by basic residues probably involved in membrane interaction. In tetrameric CPN, each CPN1 subunit might interact with the central leucine-rich repeat tandem of the cognate CPN2 subunit via a unique hydrophobic surface patch wrapping around the catalytic domain–TT interface, exposing the two active centers.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0022-2836
Last Modified: 24 Jun 2017 11:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/69990

Citation Data

Cited 28 times in Google Scholar. View in Google Scholar

Cited 32 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item