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M600149200v1
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Papers In Press, published online ahead of print February 16, 2006
J. Biol. Chem, 10.1074/jbc.M600149200
Submitted on January 6, 2006
Revised on February 7, 2006
Accepted on February 16, 2006

Dual specificity of the interfacial inhibitor brefeldin a for ARF proteins and Sec7 domains

Jean-Christophe Zeeh, Mahel Zeghouf, Cédric Grauffel, Bernard Guibert, Elyette Martin, Annick Dejaegere, and Jacqueline Cherfils

Laboratoire d'Enzymologie et Biochimie Structurales, CNRS, Gif sur Yvette, Cedex 91198

Corresponding Author: cherfils{at}lebs.cnrs-gif.fr

Guanine nucleotide exchange factors (GEFs), which activate small G proteins (SMGs) by stimulating their GDP/GTP exchange, are emerging as candidate targets for the inhibition of cellular pathways involved in diseases. However, their specific inhibition by competitive inhibitors is challenging because GEFs and SMGs families comprise highly similar members. Nature shows us an alternative strategy called interfacial inhibition, exemplified by Brefeldin A (BFA). BFA inhibits the activation of Arf1 by its GEFs in vivo by stabilizing an abortive complex between Arf-GDP and the catalytic Sec7 domain of some of its GEFs. Here we characterize the specificity of BFA towards wild-type (ARNO, BIG1) and mutant Sec7 domains and towards class I, II and III Arfs. We find that BFA-sensitivity of the exchange reaction depends on the nature of both the Sec7 domain and the Arf protein. A single Phe/Tyr substitution is sufficient to achieve BFA-sensitivity of the Sec7 domain, which is supported by our characterization of BFC, a BFA analog that cannot interact with the Tyr residue, and by free energy computations. We further show that Arf1 and Arf5, but not Arf6, are BFA-sensitive, despite their having every BFA-interacting residue in common. Analysis of Arf6 mutants points to the dynamics of the interswitch, which is involved in membrane-to-nucleotide signal propagation, as contributing to, although not sufficient for, BFA-sensitivity. Altogether, our results reveal the Tyr/Phe substitution as a novel tool for monitoring BFA sensitivity of cellular ArfGEFs, and document the exquisite and dual specificity that can be achieved by an interfacial inhibitor.


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