Protein S-sulfenylation is a fleeting molecular switch that regulates non-enzymatic oxidative folding

Amy E. M. Beedle, Steven Lynham and Sergi Garcia-Manyes ()
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Amy E. M. Beedle: King’s College London
Steven Lynham: Centre of Excellence for Mass Spectrometry, King’s College London
Sergi Garcia-Manyes: King’s College London

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract The post-translational modification S-sulfenylation functions as a key sensor of oxidative stress. Yet the dynamics of sulfenic acid in proteins remains largely elusive due to its fleeting nature. Here we use single-molecule force-clamp spectroscopy and mass spectrometry to directly capture the reactivity of an individual sulfenic acid embedded within the core of a single Ig domain of the titin protein. Our results demonstrate that sulfenic acid is a crucial short-lived intermediate that dictates the protein’s fate in a conformation-dependent manner. When exposed to the solution, sulfenic acid rapidly undergoes further chemical modification, leading to irreversible protein misfolding; when cryptic in the protein’s microenvironment, it readily condenses with a neighbouring thiol to create a protective disulfide bond, which assists the functional folding of the protein. This mechanism for non-enzymatic oxidative folding provides a plausible explanation for redox-modulated stiffness of proteins that are physiologically exposed to mechanical forces, such as cardiac titin.

Date: 2016
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DOI: 10.1038/ncomms12490

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