Kinetic mechanism of protease inhibition by alpha1-antitrypsin

Biochemical and Biophysical Research Communications
Un-Beom KangCheolju Lee

Abstract

The native form of serine protease inhibitor (serpin) is kinetically trapped in a metastable state. Metastability in these proteins is critical to inhibit target protease by forming a stable covalent complex. Despite recent determination of the crystal structures of a Michaelis protease-serpin complex as well as a stable covalent complex, details on the kinetic mechanism remain unsolved. In this report, we examined the reaction mechanism of alpha1-antitrypsin toward elastase by a combination of stopped-flow experiments via fluorescence resonance energy transfer and rapid-quench studies. The results suggest a non-covalent complex intermediate other than Michaelis complex as an intermediate before the cleavage of P1-P1' scissile bond, whose formation is the rate-determining step of the overall reaction. This rate-limiting step represents rearrangement of the reactive site loop, and is regulated by a salt bridge between E354 and R196. The ionic interaction is unique to alpha1-antitrypsin, which suggests that protease inhibition mechanisms are varied among serpins.

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Citations

Feb 10, 2006·Journal of Biochemistry and Molecular Biology·Jong-Shik ShinMyeong-Hee Yu
Jul 31, 2007·Protein Science : a Publication of the Protein Society·Je-Hyun BaekMyeong-Hee Yu
Jan 18, 2020·Biomolecules·Katarzyna SzałapataAnna Jarosz-Wilkołazka

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