Proinsulin-Processing Endopeptidases

Abstract

Knowledge of the gene structure of secreted proteins and analysis of their biosynthesis has revealed that many are initially produced as larger biologically inactive precursors that are subjected to limited proteolysis at sites marked by clusters of basic amino acids in characteristic linear sequences. Peptide hormones and neurotransmitters that are secreted via the regulated secretory pathway in neuroendocrine tissues are generally processed at pairs of basic amino acids, typically Lys Arg and Arg Arg and much less frequently at Lys Lys or Arg Lys sites. Growth factors and receptor molecules that follow the constitutive pathway are processed at sites marked by a more complex array of basic amino acids, typically a pair of basic amino acids with a further basic amino acid in the P4 position (for review, see ref. 7). In the majority of cases where the most C-terminal amino acid in the cluster is an arginine residue, cleavage of the amide bond occurs on the C-terminal side of this arginine. When it is a lysine residue, cleavage often occurs on the N-terminal side and probably involves a different enzymatic process in many cases. Basic amino acids exposed at the C-termini after endoproteolytic cleavage are removed by carboxypeptidase H (E) (CPH) within the regulated pathway of secretion. Whether a similar activity is present in the constitutive pathway is not clear.