Cystatin Superfamily Genes comprise a single evolutionary superfamily that encode protein subfamilies with functional and structural similarities that include cystatin-like sequences: Stefins (Type 1 Cystatins), Cystatins (Type 2 Cystatins), and Kininogens. Some members are active cysteine protease inhibitors; others have lost or never acquired inhibitory activity. Cystatins are intracellular or extracellular, tight, reversible, competitive inhibitors of lysosomal cysteine proteinases, such as Cathepsins B, L, H, and S, that appear to provide a protective function. Type 1 Cystatins lack disulfide bridges. Type 2 Cystatins are secreted and have 2 intrachain disulfide bonds. Kininogens contain 3 cystatin-like domains, each with 2 disulfide bonds. (NCI) [ ]