Insights into the inhibited form of the redox-sensitive SufE-like sulfur acceptor CsdE

Open Access

Abstract

Sulfur trafficking in living organisms relies on transpersulfuration reactions consisting in the enzyme-catalyzed transfer of S atoms via activated persulfidic S across protein-protein interfaces. The recent elucidation of the mechanistic basis for transpersulfuration in the CsdA-CsdE model system has paved the way for a better understanding of its role under oxidative stress. Herein we present the crystal structure of the oxidized, inactivated CsdE dimer at 2.4 Å resolution. The structure sheds light into the activation of the Cys61 nucleophile on its way from a solvent-secluded position in free CsdE to a fully extended conformation in the persulfurated CsdA-CsdE complex. Molecular dynamics simulations of available CsdE structures allow to delineate the sequence of conformational changes underwent by CsdE and to pinpoint the key role played by the deprotonation of the Cys61 thiol. The low-energy subunit orientation in the disulfide-bridged CsdE dimer demonstrates the likely physiologic relevance of this oxidative dead-end form of CsdE, suggesting that CsdE could act as a redox sensor in vivo. ; This work was supported by Spanish Instituto de Salud Carlos III (http://www.isciii.es) (PI12/01667 to MCV), Spanish Ministerio de Economía y Competitividad (http://www.mineco.gob.es/portal/site/mineco/) (PET2008_0101, BIO2009-11184, BFU2010- 22260-C02-02, and CTQ2015-66206-C2-2-R to MCV, and CTQ2015-66223-C2-2-P to IT), the Regional Government of Madrid (http://www.madrid.org/) (S2010/BD-2316 to MCV), and the European Commission (Framework Programme 7 (FP7)) (https://ec.europa.eu/research/fp7/index_en.cfm) project ComplexINC (Contract No. 279039) to MCV. F.J. Fernández (FJF) is currently employed by Abvance Biotech srl and contributed to the work presented here when affiliated to CSIC and, as an employee of Abvance, to writing and reviewing the article. Abvance Biotech srl provided support in the form of salary for author FJF, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer reviewed