Abstract
PurposeAlthough strongly related, the pathophysiological effect of the N34S mutation in the serine protease inhibitor Kazal type 1 (SPINK1) in chronic pancreatitis is still unknown. In this study, we investigate the conformational space of the human cationic trypsin-serine protease inhibitor complex.MethodsSimulations with molecular dynamics, replica exchange, and transition pathway methods are used.ResultsTwo main binding states of the inhibitor to the complex were found, which explicitly relate the influence of the mutation site to conformational changes in the active site of trypsin.ConclusionBased on our result, a hypothesis is formulated that explains the development of chronic pancreatitis through accelerated digestion of the mutant by trypsin.
Highlights
Pancreatitis is an inflammatory disorder of the pancreas
Complexed state, there are no differences in the second ary structure content, but we found that the loop region spanned by amino acids 34–38 of serine protease inhibitor Kazal type 1 (SPINK1) has distinct con formations due to the steric hindrance caused by the binding
The conformations of the TRY1-SPINK1 complex were examined in detail using molecular dynamic simulations
Summary
Pancreatitis is an inflammatory disorder of the pancreas. While acute and chronic pancreatitis were previously viewed as separated diseases, today they are regarded as a continuum, with nearly 30% of the patients exhibiting overlapping phenotypes that manifest as recurrent pancreatitis.[1]. While initial triggers for pancreatitis are diverse, almost all of them result in premature activation of trypsin and subsequently other pro teases in pancreatic acinar cells. Pancreatitis is considered to be an autodigestive disorder caused by trypsin auto-activation, which is supported by numerous mutations in the PRSS1 gene coding for human cationic trypsin (TRY1).[2,3] The serine protease inhibitor Kazal-type 1 (SPINK1, known as PSTI or TATI) represents the first line of defense against the trypsin auto-activation cascade by potently binding and inhibiting active trypsin. The inhibitor has a size of 6.2 kDa and is co-located with trypsinogen and other zymogens in storage orga nelles called zymogen granules of pancreatic acinar cells. The c.101A>G point mutation is the most common variant of the SPINK1 gene, which results in a p
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