A Conserved Hydrophobic Moiety and Helix–Helix Interactions Drive the Self-Assembly of the Incretin Analog Exendin-4

Biomolecules

Martin Wolff¹  Anja Thalhammer¹  Robert Seckler¹  Anja Schüler¹  Klaus Gast¹  Andreas Evers²  Michael Kurz²  Stefania Pfeiffer-Marek² 

[1] Department of Physical Biochemistry, University of Potsdam, D-14476 Potsdam, Germany;Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt, Germany;

关键词: biophysics;    diabetes;    peptides;    oligomerization;    conformational change;    molecular modeling;   

DOI  :  10.3390/biom11091305

来源: DOAJ

【 摘 要 】

Exendin-4 is a pharmaceutical peptide used in the control of insulin secretion. Structural information on exendin-4 and related peptides especially on the level of quaternary structure is scarce. We present the first published association equilibria of exendin-4 directly measured by static and dynamic light scattering. We show that exendin-4 oligomerization is pH dependent and that these oligomers are of low compactness. We relate our experimental results to a structural hypothesis to describe molecular details of exendin-4 oligomers. Discussion of the validity of this hypothesis is based on NMR, circular dichroism and fluorescence spectroscopy, and light scattering data on exendin-4 and a set of exendin-4 derived peptides. The essential forces driving oligomerization of exendin-4 are helix–helix interactions and interactions of a conserved hydrophobic moiety. Our structural hypothesis suggests that key interactions of exendin-4 monomers in the experimentally supported trimer take place between a defined helical segment and a hydrophobic triangle constituted by the Phe22 residues of the three monomeric subunits. Our data rationalize that Val19 might function as an anchor in the N-terminus of the interacting helix-region and that Trp25 is partially shielded in the oligomer by C-terminal amino acids of the same monomer. Our structural hypothesis suggests that the Trp25 residues do not interact with each other, but with C-terminal Pro residues of their own monomers.

【 授权许可】

Unknown