A Brief Account of Structure-Function Relationship of the Traditional Cysteine Protease Inhibitor - Cystatin with a Spec
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 o
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uman K. Nandy
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.
S.K. Nandy (*) Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal 741235, India Bioinformatics Infrastructure Facility (Bioinformatics Center), Department of Rural Development and Agricultural Production, North-Eastern Hill University, Tura Campus, Tura, Meghalaya 794002, India e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 S. Chakraborti, N.S. Dhalla (eds.), Proteases in Physiology and Pathology, DOI 10.1007/978-981-10-2513-6_27
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S.K. Nandy
Keywords
Cystatin • Cysteine protease inhibitor • Papain • C1 family • Cysteine protease
27.1 Introduction Cystatins are a group of homologous proteins [1, 2] characterized by cystatin domains, largely known for their traditional inhibitory activity toward papain (C1) families of cysteine proteases (CPs) [3, 4]. These endogenous competitive protein inhibitors form an enzymatically inactive nonobligatory complex with CPs and share a strong transient association [5, 4]. Thus, cystatins play the role of typical emergency regulators of CPs, remain separated from the target enzyme, and mostly operate on escaped host proteases or foreign proteases of pathogens to control intraand extracellular protein degradation [6, 7]. Through their competitive, reversible inhibitory activity, cystatins play crucial roles in numerous physiological and pathophysiological conditions ranging from cell survival and proliferation to differentiation, signaling, and immunomodulation [8]. In humans, decreased levels of cystatins and any kinds of imbalance t
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