Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism

Yu Nakashima, Atsushi Kawakami, Yasushi Ogasawara, Masatoshi Maeki, Manabu Tokeshi, Tohru Dairi () and Hiroyuki Morita ()
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Yu Nakashima: University of Toyama
Atsushi Kawakami: Hokkaido University
Yasushi Ogasawara: Hokkaido University
Masatoshi Maeki: Hokkaido University
Manabu Tokeshi: Hokkaido University
Tohru Dairi: Hokkaido University
Hiroyuki Morita: University of Toyama

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified peptide (RiPP) consisting of 21 amino acids with D-tryptophan at the C-terminus, and is derived from the precursor peptide MslA. MslH, encoded in the MS-271 biosynthetic gene cluster (msl), catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, leading to epi-MslA. The detailed catalytic process, including the catalytic site and cofactors, has remained enigmatic. Herein, based on X-ray crystallographic studies in association with MslA core peptide analogues, we show that MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold. The crystal structure analysis, followed by site-directed mutagenesis, docking simulation, and ICP-MS studies demonstrate that MslH employs acid/base chemistry to facilitate the reversible epimerization of the C-terminal Trp21 of MslA, by utilizing two pairs of His/Asp catalytic residues that are electrostatically tethered to a six-coordination motif with a Ca(II) ion via water molecules.

Date: 2023
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DOI: 10.1038/s41467-023-40232-x

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