Modification and Activation of Ras Proteins by Electrophilic Prostanoids with Different Structure are Site-Selective
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- 作者：Marta Renedo ; Javier Gayarre ; Carlota A. Garcí ; a-Domí ; nguez ; Andrea Pé ; rez-Rodrí ; guez ; Alicia Prieto ; F. Javier Cañ ; ada ; José ; M. Rojas ; Dolores Pé ; rez-Sala
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：June 5, 2007
- 年：2007
- 卷：46
- 期：22
- 页码：6607 - 6616
- 全文大小：595K
- 年卷期：v.46,no.22(June 5, 2007)
- ISSN：1520-4995
文摘
Cyclopentenone prostanoids (cyP) arise as important modulators of inflammation and cellproliferation. Although their physiological significance has not been fully elucidated, their potent biologicaleffects have spurred their study as leads for the development of therapeutic agents. A key determinant ofcyP 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 structuraldeterminants from the protein or the cyP that drive this modification. The results herein presented providethe first evidence that cyP with different structures target distinct thiol sites in a protein molecule, namely,H-Ras. Whereas 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) and 12-PGJ2 preferentially target theC-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-selectivemodification and activation of H-Ras in cells and the differential interaction of cyP with H, N, and K-Rasproteins. 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 preferentialinteraction of 15d-PGJ2 with H-Ras. These results put forward the possibility of influencing the selectivityof cyP-protein addition by modifying cyP structure. Furthermore, they may open new avenues for thedevelopment of cyP-based drugs.
12,14-prostaglandin J2 (15d-PGJ2) and 12-PGJ2 preferentially target theC-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-selectivemodification and activation of H-Ras in cells and the differential interaction of cyP with H, N, and K-Rasproteins. 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 preferentialinteraction of 15d-PGJ2 with H-Ras. These results put forward the possibility of influencing the selectivityof cyP-protein addition by modifying cyP structure. Furthermore, they may open new avenues for thedevelopment of cyP-based drugs.