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Structural basis for the NAD-hydrolysis mechanism and the ARTT-loop plasticity of C3 exoenzymes

¹ Institut Curie, Centre de Recherche, Paris F-75248, France
² Centre National de la Recherche Scientifique (CNRS), UMR144, Paris F-75248, France
³ INSERM U452, Faculté de médecine, 06107 Nice Cedex 2, France
⁴ Museum d'histoire naturelle, 75005 Paris, France
⁵ Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), iBiTec-S, DSV, CEA-Saclay, 91191 Gif-sur-Yvette Cedex, France

(RECEIVED December 10, 2007; FINAL REVISION February 13, 2008; ACCEPTED February 13, 2008)

C3-like exoenzymes are ADP-ribosyltransferases that specifically modify some Rho GTPase proteins, leading to their sequestration in the cytoplasm, and thus inhibiting their regulatory activity on the actin cytoskeleton. This modification process goes through three sequential steps involving NAD-hydrolysis, Rho recognition, and binding, leading to Rho ADP-ribosylation. Independently, three distinct residues within the ARTT loop of the C3 exoenzymes are critical for each of these steps. Supporting the critical role of the ARTT loop, we have shown previously that it adopts a distinct conformation upon NAD binding. Here, we present seven wild-type and ARTT loop-mutant structures of C3 exoenzyme of Clostridium botulinum free and bound to its true substrate, NAD, and to its NAD-hydrolysis product, nicotinamide. Altogether, these structures expand our understanding of the conformational diversity of the C3 exoenzyme, mainly within the ARTT loop.

Keywords: ADP-ribosyltransferase; C3 exoenzyme; ARTT loop; plasticity; crystal structures

Reprint requests to: Julie Ménétrey, Institut Curie, UMR144 26 rue d'Ulm, 75248 Paris Cedex 05, France; e-mail: julie.Menetrey{at}curie.fr; fax: 33-1-42-34-63-82; or Enrico A. Stura, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), iBiTec-S, DSV, CEA-Saclay 91191 GIF sur Yvette Cedex, France; e-mail: estura{at}cea.fr; fax: 33-1-69-08-90-71.

Abbreviations: ARTT, ADP-ribosyl toxin turn-turn; PN, phosphate-nicotinamide; NMN, nicotinamide mono-nucleotide; RMSD, root mean square deviation; GEF, guanine-exchange factor.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.073398508.

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