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♦ See referenced article, J. Biol. Chem. 2015, 290, 5947–5958
Proteolysis is an essential step in amyloidogenic fibril formation in physiological and pathophysiological conditions. Proteolysis of amyloidogenic proteins in vivo is likely to be incomplete, and the kinetics of fibril formation under conditions of partial proteolysis are not well understood. In this Paper of the Week, Wojciech Dzwolak's group at the Polish Academy of Sciences and the University of Warsaw explored the kinetics of amyloid fibrillation of insulin after partial proteolytic digestion. Partial pepsin digestion of bovine insulin resulted in an unexpected “explosive” formation of amyloidogenic fibrils. The authors identified the highly amyloidogenic insulin fragment and demonstrated that the disulfide bonds of the fragment are essential for amyloidogenesis. The authors say, “Our results point to a significant amyloidogenic potential of insulin molecule being ‘unleashed’ upon cutting open its central topological loop.” Understanding amyloid fibrillation after limited proteolysis, which may mimic physiological conditions, is an important step in deciphering this process in vivo.