Abstract
The selectivity of cathepsin D, a mammalian intracellular aspartyl proteinase involved in the degradation of endocytosed proteins, was studied. For this purpose, several proteins of known primary structure were subjected to mild proteolysis by the enzyme, and the preferentially cleaved peptide bonds were identified. Comparison of the primary structures around these sites indicates that cathepsin D shows a strong preference for peptide bonds within a distinct sequence pattern of amino acids extending over 7 residues. In general, this pattern is most likely to occur within amphipathic alpha-helical structures. These findings and their possible implications are discussed together with additional evidence suggesting an important role for cathepsin D in the processing of protein antigens, an essential step for their recognition by T-cells. Accordingly, it is proposed that the proteolytic activity of cathepsin D is crucial in selecting processing sites and hence the location and structural context of T-cell epitopes for the majority of protein antigens.
Highlights
The selectivity of cathepsin D, a mammalian intra- of help in predicting the products of processing and, cellular aspartyl proteinase involved in the degrada- the location and structural context of T-cell epitopes
It is proposed that the proteo- This suggests that thespecificity of the enzyme depends not lyticactivity of cathepsin D is crucial in selecting only on the amino acid residues directly flanking the scissle processing sites and the location and structural bond and onprimary or even higher order structural context of T-cell epitopes for the majority of protein features of the substratewhich involve other amino acids
Mild Digestion with Cathepsin D-For most of the protein substrates studied, incubation with cathepsin D under mildly acidic conditions led to therapid release of fragments, among which only a few were obtained in relatively high yield after an incubation period of 1or 2 h
Summary
The selectivity of cathepsin D, a mammalian intra- of help in predicting the products of processing and, cellular aspartyl proteinase involved in the degrada- the location and structural context of T-cell epitopes. It is tion of endocytosed proteins, was studied. It is proposed that the proteo- This suggests that thespecificity of the enzyme depends not lyticactivity of cathepsin D is crucial in selecting only on the amino acid residues directly flanking the scissle processing sites and the location and structural bond and onprimary or even higher order structural context of T-cell epitopes for the majority of protein features of the substratewhich involve other amino acids. This study, like many others (reviewed in I), involved proteolysis at pH3.5 during prolonged
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