RT Journal Article
SR Electronic
T1 The N34S mutation of SPINK1 may impact the kinetics of trypsinogen activation to cause early trypsin release in the pancreas
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.21.262162
DO 10.1101/2020.08.21.262162
A1 Zhuyezi Sun
A1 István Kolossváry
A1 Dima Kozakov
A1 Miklós Sahin-Tóth
A1 Sandor Vajda
YR 2020
UL http://biorxiv.org/content/early/2020/08/23/2020.08.21.262162.abstract
AB The N34S variant of the trypsin inhibitor SPINK1 is the clinically most significant risk factor for chronic pancreatitis, but the underlying molecular mechanism could not be identified. Molecular dynamics simulations and docking of the generated conformational ensemble of SPINK1 to trypsin show that the mutation reduces the fraction of conformations that can directly participate in productive association, thereby reducing the association rate. The small change is difficult to detect by measuring the kinetics of SPINK1 binding to trypsin. However, kinetic modeling reveals that even a small change in the inhibition rate affects the trypsinogen to trypsin conversion rate at the early stage of the reaction when the trypsin concentration is very low, and the impact is substantially amplified by the autocatalytic mechanism of the conversion. Thus, the slightly reduced inhibition rate shortens the delay in the activation of trypsin release, which is therefore occurs within the pancreas.Competing Interest StatementThe authors have declared no competing interest.