Abstract
BackgroundThe unique S28 family of proteases is comprised of the carboxypeptidase PRCP and the aminopeptidase DPP7. The structural basis of the different substrate specificities of the two enzymes is not understood nor has the structure of the S28 fold been described.ResultsThe experimentally phased 2.8 Å crystal structure is presented for human PRCP. PRCP contains an α/β hydrolase domain harboring the catalytic Asp-His-Ser triad and a novel helical structural domain that caps the active site. Structural comparisons with prolylendopeptidase and DPP4 identify the S1 proline binding site of PRCP. A structure-based alignment with the previously undescribed structure of DPP7 illuminates the mechanism of orthogonal substrate specificity of PRCP and DPP7. PRCP has an extended active-site cleft that can accommodate proline substrates with multiple N-terminal residues. In contrast, the substrate binding groove of DPP7 is occluded by a short amino-acid insertion unique to DPP7 that creates a truncated active site selective for dipeptidyl proteolysis of N-terminal substrates.ConclusionThe results define the structure of the S28 family of proteases, provide the structural basis of PRCP and DPP7 substrate specificity and enable the rational design of selective PRCP modulators.
Highlights
The unique S28 family of proteases is comprised of the carboxypeptidase PRCP and the aminopeptidase dipeptidyl peptidase 7 (DPP7)
The structural basis of catalytic mechanism, substrate specificity and rational drug design has been identified for numerous protease families, there has been no structural description of the S28 family of proteases that form a distinct branch of the serine carboxypeptidase clan
The structure of the human carboxypeptidase PRCP presented here provides the first structural description of the S28 family of proteases. These proteases consist of a conserved α/β hydrolase domain and a novel structural domain that caps the active site
Summary
The unique S28 family of proteases is comprised of the carboxypeptidase PRCP and the aminopeptidase DPP7. The human protease tree is comprised of at least 676 diverse proteins that have been systematically organized into clans and families based on similarity in sequence, structure, and function [1]. The structural basis of catalytic mechanism, substrate specificity and rational drug design has been identified for numerous protease families, there has been no structural description of the S28 family of proteases that form a distinct branch of the serine carboxypeptidase clan. PRCP is a lysosomal, serine carboxypeptidase that cleaves hydrophobic C-terminal amino acids adjacent to proline [5,6]. DPP7 is a serine dipeptidyl aminopeptidase that cleaves N-terminal amino acids adjacent to proline and is localized to intracellular vesicles [3]
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