Carboxypeptidases from A to Z: implications in embryonic development and Wnt binding

Abstract

Carboxypeptidases perform many diverse functions in the body. The well-studied pancreatic enzymes (carboxypeptidases A1, A2 and B) are involved in the digestion of food, whereas a related enzyme (mast-cell carboxypeptidase A) functions in the degradation of other proteins. Several members of the metallocarboxypeptidase gene family (carboxypeptidases D, E, M and N) are more selective enzymes and are thought to play a role in the processing of intercellular peptide messengers. Three other members of the metallocarboxypeptidase gene family do not appear to encode active enzymes; these members have been designated CPX-1, CPX-2 and AEBP1/ACLP. In this review, we focus on the recently discovered carboxypeptidase Z (CPZ). This enzyme removes C-terminal Arg residues from synthetic substrates, as do many of the other members of the gene family. However, CPZ differs from the other enzymes in that CPZ is enriched in the extracellular matrix and is broadly distributed during early embryogenesis. In addition to containing a metallocarboxypeptidase domain, CPZ also contains a Cys-rich domain that has homology to Wnt-binding proteins; Wnts are important signaling molecules during development. Although the exact function of CPZ is not yet known, it is likely that this protein plays a role in development by one of several possible mechanisms.

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

“…Empirical evidence suggests it lacks catalytic activity [3] and this finding is consistent with sequence alignments which reveal substitution of two residues critical for substrate binding (R117 and Y248 in CPB are replaced by Val and His residues, V408 and H558, in CPX-1) [2,3]. Thus, the molecular role and biological function of CPX-1 are unclear.…”

“…The M14 family of metallocarboxypeptidases is the largest family of CPs and most, but not all, are active as peptidases [1]. The carboxypeptidase E (CPE) subfamily consists of eight members, of which five are enzymatically active peptidases [2]. The three members that lack catalytic activity, CPX-1, CPX-2 and aortic carboxypeptidase-like protein/adipocyte enhancer binding protein 1 (ACLP/AEBP1) form a discrete subset [2].…”

“…The carboxypeptidase E (CPE) subfamily consists of eight members, of which five are enzymatically active peptidases [2]. The three members that lack catalytic activity, CPX-1, CPX-2 and aortic carboxypeptidase-like protein/adipocyte enhancer binding protein 1 (ACLP/AEBP1) form a discrete subset [2]. Their CP domains show the highest degree of homology within the family with each lacking one or more residues critical for enzymatic activity and/or substrate binding [2,3,4].…”

“…The three members that lack catalytic activity, CPX-1, CPX-2 and aortic carboxypeptidase-like protein/adipocyte enhancer binding protein 1 (ACLP/AEBP1) form a discrete subset [2]. Their CP domains show the highest degree of homology within the family with each lacking one or more residues critical for enzymatic activity and/or substrate binding [2,3,4]. Furthermore, each contains an N-terminal signal peptide followed by a discoidin domain (DSD), a domain not present in the other family members [2].…”

Identification of inhibitors using a cell-based assay for monitoring Golgi-resident protease activity

“…This process of pro-protein maturation involves recognition and cleavage of unique sequences in target protein prodomains by specific proteases [11]. TGN resident proteases include carboxypeptidases [12], prohormone convertase (PC) family members [10;11], and β-site amyloid precursor protein (BACE) family members [13].…”