Mechanistic insights into intramembrane proteolysis by E. coli site-2 protease homolog RseP

Yuki Imaizumi, Kazunori Takanuki, Takuya Miyake, Mizuki Takemoto, Kunio Hirata, Mika Hirose, Rika Oi, Tatsuya Kobayashi, Kenichi Miyoshi, Rie Aruga, Tatsuhiko Yokoyama, Shizuka Katagiri, Hiroaki Matsuura, Kenji Iwasaki, Takayuki Kato, Mika K. Kaneko, Yukinari Kato, Michiko Tajiri, Satoko Akashi, Osamu NurekiYohei Hizukuri, Yoshinori Akiyama, Terukazu Nogi

研究成果: ジャーナルへの寄稿学術論文査読

7 被引用数 (Scopus)

抄録

Site-2 proteases are a conserved family of intramembrane proteases that cleave transmembrane substrates to regulate signal transduction and maintain proteostasis. Here, we elucidated crystal structures of inhibitor-bound forms of bacterial site-2 proteases including Escherichia coli RseP. Structure-based chemical modification and cross-linking experiments indicated that the RseP domains surrounding the active center undergo conformational changes to expose the substrate-binding site, suggesting that RseP has a gating mechanism to regulate substrate entry. Furthermore, mutational analysis suggests that a conserved electrostatic linkage between the transmembrane and peripheral membrane-associated domains mediates the conformational changes. In vivo cleavage assays also support that the substrate transmembrane helix is unwound by strand addition to the intramembrane β sheet of RseP and is clamped by a conserved asparagine residue at the active center for efficient cleavage. This mechanism underlying the substrate binding, i.e., unwinding and clamping, appears common across distinct families of intramembrane proteases that cleave transmembrane segments.

本文言語英語
論文番号eabp9011
ジャーナルScience advances
8
34
DOI
出版ステータス出版済み - 2022 8月

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