Molecular origin of the self-assembly of lanreotide into nanotubes: a mutational approach.
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 beta-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.
Valéry
Céline
C
Ipsen Pharma, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
Pouget
Emilie
E
Pandit
Anjali
A
Verbavatz
Jean-Marc
JM
Bordes
Luc
L
Boisdé
Isabelle
I
Cherif-Cheikh
Roland
R
Artzner
Franck
F
Paternostre
Maité
M
D000595:Amino Acid Sequence; D024322:Amino Acids, Aromatic / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry; D001665:Binding Sites; D019617:Halobacterium salinarum / Q000737:chemistry / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000737:chemistry; D008853:Microscopy; D008969:Molecular Sequence Data; D009154:Mutation; D045333:Nanotubes, Peptide / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D012996:Solutions / Q000737:chemistry; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D014867:Water / Q000737:chemistry
D024322:Amino Acids, Aromatic; D000682:Amyloid; D045333:Nanotubes, Peptide; D010456:Peptides, Cyclic; D012996:Solutions; D014867:Water; C060347:lanreotide; D013004:Somatostatin; D008239:Lysine