An Overview of Endoplasmic Reticulum Calpain System
Calpains, a family of Ca2+-dependent cysteine proteases, can modulate their substrates structure and function through limited proteolytic activity. Calpain mediated proteolysis of intracellular proteins is a key step in various cellular processes such as
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Abstract Calpains, a family of Ca2+-dependent cysteine proteases, can modulate their substrates structure and function through limited proteolytic activity. Calpain mediated proteolysis of intracellular proteins is a key step in various cellular processes such as cytoskeleton modulation, cell migration, cell cycle progression and apoptosis. Calpain activity is controlled in vivo by calpastatin, a multiheaded endogenous polypeptide encoded by the calpastatin gene that specifically inhibits calpain. Calpains have previously been considered as the cytoplasmic enzymes; however, recent research have demonstrated that m-calpain and calpastatin are present in endoplasmic reticulum and play important roles in a variety of pathophysiological conditions including necrotic and apoptotic cell death phenomena. This review summarizes function and regulation of the endoplasmic reticulum calpain system, focusing on the relevance of its roles in several cellular and biochemical events under normal and some pathophysiological conditions. Keywords Endoplasmic reticulum • Calcium • m-calpain • Calpastatin • Apoptosis
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Introduction
Since the first description of calpain (calcium-activated neutral protease) in 1964 by Guroff [1], extensive progress has been made regarding the identity, structure, activity, localization, and physiological and pathological functions of calpains. To date, the
K. Samanta • P. Kar Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX13PT, UK T. Chakraborti • S. Chakraborti (*) Department of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India e-mail: [email protected]; [email protected] S. Chakraborti and N.S. Dhalla (eds.), Proteases in Health and Disease, Advances in Biochemistry in Health and Disease 7, DOI 10.1007/978-1-4614-9233-7_1, © Springer Science+Business Media New York 2013
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number of identified mammalian calpain protease family members has grown to 14 [2]. Based on their tissue expression patterns, calpains are classified as ubiquitous or tissue specific [3]. Two ubiquitous isoforms, μ- and m-calpains and their endogenous inhibitor, calpastatin have been identified and studied extensively. The interaction of calpastatin with calpain prevents both activation and catalytic activity of calpain [4]. In vitro studies have shown that calpain and calpain fragments bind to calpastatin and that calpastatin fragments bind to calpain in the presence of Ca2+ [5]. Intracellular Ca2+ is a critical signal transduction element in regulating pulmonary smooth muscle contraction, proliferation as well as expression of a variety of gene responsible for pulmonary hypertension [6]. Cytosolic Ca2+ dynamics is regulated, at least partly, by the ER, which takes up when cytosolic Ca2+ levels are high and releases it when cytosolic Ca2+ levels are low [7]. The endoplasmic reticulum (ER) is one of the largest sub-organelles in eukaryotic cells. In the ER, the essential function of m
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