The cystatins: a diverse superfamily of cysteine peptidase inhibitors

Abstract

The cystatins comprise a homologous group of protein inhibitors of peptidases, of which the first to be studied in detail was chicken cystatin from egg-white. Three distinct protein families or "types" are recognized within the cystatin superfamily. The type 1 cystatins (also called "stefins") are the simplest in structure, being single chains of about 100 amino acids, with no disulphide bonds or carbohydrate. The Type 2 cystatins, which include the egg-white protein, have about 115 amino acids, and two disulphide loops, but still no carbohydrate. The Type 3 cystatins are the plasma kininogens in which each molecule contains three divergent copies of the typical cystatin sequence differing in activity as well as structure; these complex inhibitor molecules contain disulphide bonds and also carbohydrate groups. The cystatins inhibit most cysteine endopeptidases of the papain type, and also the exopeptidase dipeptidyl peptidase I. Each cystatin molecule has a single reactive site for all the peptidases it inhibits, but there are large differences in K(i) values for different combinations of cystatin and enzyme, and calpains are inhibited only by one of the segments of the kininogens. The cystatins have many important characteristics in common, but their differences in molecular structure imply different routes of biosynthesis, are associated with different in vivo distributions, and suggest a variety of physiological functions.