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Title

Modification and activation of Ras proteins by electrophilic prostanoids with different structure are site-selective

AuthorsRenedo, Marta; Gayarre, Javier; García-Domínguez, Carlota A.; Pérez-Rodríguez, Andrea; Prieto, Alicia ; Cañada, F. Javier ; Rojas, José M.; Pérez-Sala, Dolores
Issue Date2007
PublisherAmerican Chemical Society
CitationBiochemistry 46(22):6607-6616(2007)
AbstractCyclopentenone prostanoids (cyP) arise as important modulators of inflammation and cell proliferation. Although their physiological significance has not been fully elucidated, their potent biological effects have spurred their study as leads for the development of therapeutic agents. A key determinant of cyP action is their ability to bind to thiol groups in proteins or in glutathione through Michael addition. Even though several protein targets for cyP addition have been identified, little is known about the structural determinants from the protein or the cyP that drive this modification. The results herein presented provide the first evidence that cyP with different structures target distinct thiol sites in a protein molecule, namely, H-Ras. Whereas 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and Δ12-PGJ2 preferentially target the C-terminal region containing cysteines 181 and 184, PGA1 and 8-iso-PGA1 bind mainly to cysteine 118, located in the GTP-binding motif. The biological counterparts of this specificity are the site-selective modification and activation of H-Ras in cells and the differential interaction of cyP with H, N, and K-Ras proteins. Cysteine 184 is unique to H-Ras, whereas cysteine 118 is present in the three Ras homologues. Consistent with this, PGA1 binds to and activates H-, N-, and K-Ras, thus differing from the preferential interaction of 15d-PGJ2 with H-Ras. These results put forward the possibility of influencing the selectivity of cyP-protein addition by modifying cyP structure. Furthermore, they may open new avenues for the development of cyP-based drugs. © 2007 American Chemical Society.
URIhttp://hdl.handle.net/10261/77731
DOI10.1021/bi602389p
Identifiersdoi: 10.1021/bi602389p
issn: 0006-2960
e-issn: 1520-4995
Appears in Collections:(CIB) Artículos
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