Viscous drag as the source of active site perturbation during protease translocation: insights into how inhibitory processes are controlled by serpin metastability

Journal of Molecular Biology
Jong-Shik Shin, Myeong-Hee Yu

Abstract

The native form of serine protease inhibitors (serpins) is kinetically trapped in a metastable state, which is thought to play a central role in the inhibitory mechanism. The initial binding complex between a serpin and a target protease undergoes a conformational change that forces the protease to translocate toward the opposite pole. Although structural determination of the final stable complex revealed a detailed mechanism of keeping the bound protease in an inactive conformation, it has remained unknown how the serpin exquisitely translocates a target protease with an acyl-linkage unhydrolyzed. We previously suggested that the acyl-linkage hydrolysis is strongly suppressed by active site perturbation during the protease translocation. Here, we address what induces the transient perturbation and how the serpin metastability contributes to the perturbation. Inhibitory activity of alpha1-antitrypsin (alpha1AT) toward elastase showed negative correlations with medium viscosity and Stokes radius of elastase moiety, indicating that viscous drag directly affects the protease translocation. Stopped-flow measurements revealed that the change in the inhibitory activity is primarily caused by the change in the translocation rate. The ...Continue Reading

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Citations

Mar 7, 2009·Journal of Molecular Biology·Stefano RicagnoMartino Bolognesi
Oct 27, 2007·Protein Science : a Publication of the Protein Society·Lu LiuAnne Gershenson
Aug 1, 2010·Biomolecular Concepts·Sonia CacciaMartino Bolognesi

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