INQUIMAE   12526
INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
artículos
Título:
Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families
Autor/es:
DEFELIPE, LUCAS ALFREDO; LANZAROTTI, ESTEBAN; GAUTO, DIEGO; MARTI, MARCELO ADRIÁN; TURJANSKI, ADRIAN GUSTAVO
Revista:
PLOS COMPUTATIONAL BIOLOGY
Editorial:
PUBLIC LIBRARY SCIENCE
Referencias:
Lugar: San Francisco; Año: 2015 vol. 11
ISSN:
1553-734X
Resumen:
Cysteine
residues have a rich chemistry and play a critical role in the catalytic
activity of a plethora of enzymes. However, cysteines are susceptible
to oxidation by Reactive Oxygen and Nitrogen Species, leading to a loss of their catalytic function. Therefore, cysteine oxidation is emerging as a relevant physiological regulatory mechanism. Formation of a cyclic sulfenyl amide residue at the active site of redox-regulated proteins has been proposed as a protection mechanism against irreversible oxidation as the sulfenyl amide intermediate has been identified in several proteins. However, how and why only some specific cysteine
residues in particular proteins react to form this intermediate is
still unknown. In the present work using in-silico based tools, we have
identified a constrained conformation that accelerates sulfenyl amide formation.
By means of combined MD and QM/MM calculation we show that this
conformation positions the NH backbone towards the sulfenic acid and
promotes the reaction to yield the sulfenyl amide
intermediate, in one step with the concomitant release of a water
molecule. Moreover, in a large subset of the proteins we found a
conserved beta sheet-loop-helix motif, which is present across different
protein folds, that is key for sulfenyl amide production as it promotes the previous formation of sulfenic acid. For catalytic activity, in several cases, proteins need the Cysteine
to be in the cysteinate form, i.e. a low pKa Cys. We found that the
conserved motif stabilizes the cysteinate by hydrogen bonding to several
NH backbone moieties. As cysteinate is also more reactive toward ROS we
propose that the sheet-loop-helix motif and the constraint conformation
have been selected by evolution for proteins that need a reactive Cys
protected from irreversible oxidation. Our results also highlight how fold conservation can be correlated to redox chemistry regulation of protein function.