A Brief Account of Structure-Function Relationship of the Traditional Cysteine Protease Inhibitor - Cystatin with a Special Focus on Human Family 1 and 2 Cystatins

Abstract

Cystatins are well-documented cysteine protease inhibitors with highly conserved structural folds, distributed in a variety of species. Involvement of cystatin in various biochemical pathways through regulation of protein degradation makes it an element of amazing therapeutic possibilities for treatment of a broad range of diseases. Cystatin superfamily has been divided into four groups: stefins or family 1; cystatins or family 2; kininogens or family 3; and family 4 cystatin. The cystatin superfamily shares a common cystatin fold constituting five antiparallel β-sheets enfolded around a five-turn α-helix forming a cuneus-shaped structure that blocks the access of the active site of papain-like cysteine proteases (CPs). Crystallographic and mutagenesis studies identify three conserved regions mainly involved in the interaction with papain (C1) family of CPs, namely, (a) N-terminal region, (b) L1 loop, and (c) L2 loop. Despite sharing the same structural fold and inhibiting through the same mechanism, cystatin demonstrates huge variation in inhibitory affinity toward C1 family of CPs. Relative contribution and sequential dissimilarity of three conserved sites controlled the diverse interaction patterns of cystatins, which in turn determined the wide-ranging affinity of cystatins toward papain family of CPs. Some of the members of family 2 cystatins show additional affinity toward legumain family of CPs through an alternate binding site compared to papains.