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Molecular Origin of the Self-Assembly of Lanreotide into Nanotubes: A Mutational Approach

Céline Valéry ^*, Emilie Pouget , Anjali Pandit , Jean-Marc Verbavatz , Luc Bordes , Isabelle Boisdé , Roland Cherif-Cheikh ^*, Franck Artzner  and Maité Paternostre 

^* Ipsen Pharma, 08980 Sant Feliu de Llobregat, Barcelona, Spain; Unité mixte de Recherche du Centre National pour la Recherche Scientifique 6626, Université Rennes 1, F-35042 Rennes, France; and Institut de Bio Technologies de Saclay, Commisariat à l'Energie Atomique et Centre National pour la Recherche Scientifique, F-91191 Gif-sur-Yvette, France

Correspondence: Address reprint requests to Maité Paternostre, Institut de BioTechnologies de Saclay, CEA-Saclay, URA 2096, 91191 Gif-sur-Yvette, France. Tel.: 33-1-69-08-67-49; Fax: 33-1-69-08-43-89; E-mail: maite.paternostre{at}cea.fr.

Lanreotide, a synthetic, therapeutic octapeptide analog of somatostatin, self-assembles in water into perfectly hollow and monodisperse (24-nm wide) nanotubes. Lanreotide is a cyclic octapeptide that contains three aromatic residues. The molecular packing of the peptide in the walls of a nanotube has recently been characterized, indicating four hierarchical levels of organization. This is a fascinating example of spontaneous self-organization, very similar to the formation of the gas vesicle walls of Halobacterium halobium. However, this unique peptide self-assembly raises important questions about its molecular origin. We adopted a directed mutation approach to determine the molecular parameters driving the formation of such a remarkable peptide architecture. We have modified the conformation by opening the cycle and by changing the conformation of a Lys residue, and we have also mutated the aromatic side chains of the peptide. We show that three parameters are essential for the formation of lanreotide nanotubes: i), the specificity of two of the three aromatic side chains, ii), the spatial arrangement of the hydrophilic and hydrophobic residues, and iii), the aromatic side chain in the β-turn of the molecule. When these molecular characteristics are modified, either the peptides lose their self-assembling capability or they form less-ordered architectures, such as amyloid fibers and curved lamellae. Thus we have determined key elements of the molecular origins of lanreotide nanotube formation.