Serpins are a widely distributed family of high molecular mass protein proteinase inhibitors that can inhibit both serine and cysteine proteinases by a remarkable mechanism-based kinetic trapping of an acyl or thioacyl enzyme intermediate that involves massive conformational transformation. The trapping is based on distortion of the proteinase in the complex, with energy derived from the unique metastability of the active serpin. Serpins are the favoured inhibitors for regulation of proteinases in complex proteolytic cascades, such as are involved in blood coagulation, fibrinolysis and complement activation, by virtue of the ability to modulate their specificity and reactivity. Given their prominence as inhibitors, much work has been carried out to understand not only the mechanism of inhibition, but how it is fine-tuned, both spatially and temporally. The metastability of the active state raises the question of how serpins fold, whereas the misfolding of some serpin variants that leads to polymerization and pathologies of liver disease, emphysema and dementia makes it clinically important to understand how such polymerization might occur. Finally, since binding of serpins and their proteinase complexes, particularly plasminogen activator inhibitor-1 (PAI-1), to the clearance and signalling receptor LRP1 (low density lipoprotein receptor-related protein 1), may affect pathways linked to cell migration, angiogenesis, and tumour progression, it is important to understand the nature and specificity of binding. The current state of understanding of these areas is addressed here.
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August 2016
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A schematic representation for the process of mitophagy in skeletal muscle. For a detailed coverage of the regulation of mitochondrial function in muscle, see the review by Hood et al. (Volume 473, Issue 15, pages 2295–2314). - PDF Icon PDF LinkFront Matter
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Review Article|
July 28 2016
Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance
Peter G.W. Gettins;
Peter G.W. Gettins
1
*Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, U.S.A.
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Steven T. Olson
Steven T. Olson
1
†Center for Molecular Biology of Oral Diseases and Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 22 2016
Revision Received:
March 24 2016
Accepted:
March 31 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (15): 2273–2293.
Article history
Received:
January 22 2016
Revision Received:
March 24 2016
Accepted:
March 31 2016
Citation
Peter G.W. Gettins, Steven T. Olson; Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance. Biochem J 1 August 2016; 473 (15): 2273–2293. doi: https://doi.org/10.1042/BCJ20160014
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