Conformational Remodeling Enhances Activity of Lanthipeptide Zinc-metallopeptidases

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2022 May 5

PMID 35513512

Authors

Chang Zhao

Wangjian Sheng

Ying Wang

Jie Zheng

Xiangqian Xie

Yong Liang

Wanqing Wei

Rui Bao

Huan Wang

Affiliations

Soon will be listed here.

Abstract

Lanthipeptides are an important group of natural products with diverse biological functions, and their biosynthesis requires the removal of N-terminal leader peptides (LPs) by designated proteases. LanP enzymes, a subgroup of M1 zinc-metallopeptidases, have been recently identified as bifunctional proteases with both endo- and aminopeptidase activities to remove LPs of class III and class IV lanthipeptides. Herein, we report the biochemical and structural characterization of EryP as the LanP enzyme from the biosynthesis of class III lanthipeptide erythreapeptin. We determined X-ray crystal structures of EryP in three conformational states, the open, intermediate and closed states, and identified a unique interdomain Ca binding site as a regulatory element that modulates its domain dynamics and proteolytic activity. Inspired by this regulatory Ca binding, we developed a strategy to engineer LanP enzymes for enhanced catalytic activities by strengthening interdomain associations and driving the conformational equilibrium toward their closed forms.

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