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Abstract:

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. © 2015 Defelipe et al.

Registro:

Documento: Artículo
Título:Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families
Autor:Defelipe, L.A.; Lanzarotti, E.; Gauto, D.; Marti, M.A.; Turjanski, A.G.
Filiación:Departamento de Química Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina
INQUIMAE/UBA-CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:acid; amide; carbon nitrogen hydrolase; cysteine; DJ 1 protein; glutamine amidotransferase; hydrolase; phosphatase; protein tyrosine phosphatase; SNO glutamine amidotransferase; sulfenic acid; sulfenyl amide; thiosulfate sulfurtransferase; transferase; unclassified drug; amide; cysteine; protein; sulfenic acid derivative; amino acid analysis; Article; catalysis; chemical analysis; chemical structure; conformational transition; controlled study; molecular dynamics; molecular evolution; oxidation reduction reaction; protein folding; protein function; protein localization; reaction time; residue analysis; sequence analysis; biology; chemistry; metabolism; molecular model; oxidation reduction reaction; protein conformation; Amides; Computational Biology; Cysteine; Models, Molecular; Oxidation-Reduction; Protein Conformation; Proteins; Sulfenic Acids
Año:2015
Volumen:11
Número:3
DOI: http://dx.doi.org/10.1371/journal.pcbi.1004051
Título revista:PLoS Computational Biology
Título revista abreviado:PLoS Comput. Biol.
ISSN:1553734X
CAS:amide, 17655-31-1; cysteine, 4371-52-2, 52-89-1, 52-90-4; hydrolase, 9027-41-2; phosphatase, 9013-05-2; protein tyrosine phosphatase, 79747-53-8, 97162-86-2; thiosulfate sulfurtransferase, 9026-04-4; transferase, 9047-61-4; protein, 67254-75-5; Amides; Cysteine; Proteins; Sulfenic Acids
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_1553734X_v11_n3_p_Defelipe

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Citas:

---------- APA ----------
Defelipe, L.A., Lanzarotti, E., Gauto, D., Marti, M.A. & Turjanski, A.G. (2015) . Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families. PLoS Computational Biology, 11(3).
http://dx.doi.org/10.1371/journal.pcbi.1004051
---------- CHICAGO ----------
Defelipe, L.A., Lanzarotti, E., Gauto, D., Marti, M.A., Turjanski, A.G. "Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families" . PLoS Computational Biology 11, no. 3 (2015).
http://dx.doi.org/10.1371/journal.pcbi.1004051
---------- MLA ----------
Defelipe, L.A., Lanzarotti, E., Gauto, D., Marti, M.A., Turjanski, A.G. "Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families" . PLoS Computational Biology, vol. 11, no. 3, 2015.
http://dx.doi.org/10.1371/journal.pcbi.1004051
---------- VANCOUVER ----------
Defelipe, L.A., Lanzarotti, E., Gauto, D., Marti, M.A., Turjanski, A.G. Protein Topology Determines Cysteine Oxidation Fate: The Case of Sulfenyl Amide Formation among Protein Families. PLoS Comput. Biol. 2015;11(3).
http://dx.doi.org/10.1371/journal.pcbi.1004051