Abstract
Eukaryotic aminopeptidase P1 (APP1), also known as X-prolyl aminopeptidase (XPNPEP1) in human tissues, is a cytosolic exopeptidase that preferentially removes amino acids from the N-terminus of peptides possessing a penultimate N-terminal proline residue. The enzyme has an important role in the catabolism of proline containing peptides since peptide bonds adjacent to the imino acid proline are resistant to cleavage by most peptidases. We show that recombinant and catalytically active Caenorhabditis elegans APP-1 is a dimer that uses dinuclear zinc at the active site and, for the first time, we provide structural information for a eukaryotic APP-1 in complex with the inhibitor, apstatin. Our analysis reveals that C. elegans APP-1 shares similar mode of substrate binding and a common catalytic mechanism with other known X-prolyl aminopeptidases.
Highlights
Metallopeptidases make up around a third of all known proteolytic enzymes and use an activated water molecule coordinated to a divalent metal ion as the catalytic nucleophile for peptide bond hydrolysis [1,2]
Our analysis reveals that C. elegans APP-1 shares similar mode of substrate binding and a common catalytic mechanism with other known X-prolyl aminopeptidases
In this paper we have presented the structure of C. elegans APP-1 both in its native form as well as in complex with the inhibitor, apstatin
Summary
Metallopeptidases make up around a third of all known proteolytic enzymes and use an activated water molecule coordinated to a divalent metal ion as the catalytic nucleophile for peptide bond hydrolysis [1,2]. The active sites of most metalloproteases contain a single metal ion; enzymes belonging to the M24 family possess two metal ions that co-catalytically activate a bridging water molecule [2]. Proline is different from the other common proteinogenic amino acids in that it is an imino acid where the side chain is part of a five-membered ring that includes both the Ca and the amino nitrogen atom. As a consequence of the conformational rigidity conferred by the cyclic side-chain, peptide bonds involving proline are often resistant to hydrolysis by peptidases [5,6]. There is a need for proline-specific peptidases that can be used strategically to terminate the activity of peptide hormones (e.g. bradykinin) and for the catabolism of peptides derived from proline-rich proteins, such as collagen [7,8,9]
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