Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz-Domain Inhibitors
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REVIEW
Evolutionary Aspects of the Structural Convergence and Functional Diversification of Kunitz‑Domain Inhibitors Manasi Mishra1 Received: 24 December 2019 / Accepted: 4 July 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Kunitz-type domains are ubiquitously found in natural systems as serine protease inhibitors or animal toxins in venomous animals. Kunitz motif is a cysteine-rich peptide chain of ~ 60 amino acid residues with alpha and beta fold, stabilized by three conserved disulfide bridges. An extensive dataset of amino acid variations is found on sequence analysis of various Kunitz peptides. Kunitz peptides show diverse biological activities like inhibition of proteases of other classes and/or adopting a new function of blocking or modulating the ion channels. Based on the amino acid residues at the functional site of various Kunitz-type inhibitors, it is inferred that this ‘flexibility within the structural rigidity’ is responsible for multiple biological activities. Accelerated evolution of functional sites in response to the co-evolving molecular targets of the hosts of venomous animals or parasites, gene sharing, and gene duplication have been discussed as the most likely mechanisms responsible for the functional heterogeneity of Kunitz-domain inhibitors. Keywords Kunitz domain · Serine protease inhibitor · Venom toxins · Kvion channel inhibitor · Molecular evolution · Natural selection
Introduction: Elucidating the Structural and Functional Biodiversity of Kunitz Domain Peptidases are indispensable for the survival of all kinds of organisms as they break down substrate proteins but their activities need to be kept under strict control. Inhibitors of peptidases, the protease inhibitors play crucial roles in natural systems by tightly regulating the protease activity and acting as a switch in many signaling pathways (Laskowski and Kato 1980; Rawlings et al. 2004a). Several inherited diseases have been attributed to the abnormalities in the functioning of proteases and their inhibitors (Molinari et al. 2003; Fregonese and Stalk 2008; Cleynen et al. 2011; Ketterer et al. 2016). Protease inhibitors have been classified either by their mechanism of action or by the type of Handling editor: Erich Bornberg-Bauer. * Manasi Mishra [email protected]; [email protected] 1
Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Gautam Buddha Nagar, Uttar Pradesh 201314, India
protease they inhibit: aspartic, cysteine, metallo, serine, and threonine inhibitors (Laskowski and Kato 1980). They can be also classified into families/superfamilies based on the similarities at the amino acid sequence level and/or tertiary structure (Rawlings et al. 2004a). Similarities in primary structure and tertiary structure have supported the common ancestry of many inhibitor families. The research on protease inhibitors has always been in attention owing to their potential applications in medicine, agriculture, and biotechnology (Sabotič and Kos 2012;
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