Effect of a Single-Point Mutation on the Conformation and Dynamics of Islet Amyloid Polypeptide from Nanosecond-Resolved Intramolecular Contact Formation

Abstract

Islet amyloid polypeptide (IAPP) is an intrinsically disordered protein involved in regulating glucose metabolism and gastric emptying. It plays a crucial role in beta cell failure in diabetes type II, where it accumulates in the form of amyloid fibers. Human IAPP (hIAPP) is arguably the most amyloidogenic naturally occurring peptide known so far. Recent work by Raleigh and coworkers shows that a single-point mutation (I26P) converts it into an effective in vitro amyloid inhibitor1,2. The I26P mutation has been proposed to inhibit fibril formation by affecting the ability of the disordered C terminal tail to rearrange into the amyloid fibril structure, while maintaining intact the conformational properties of the N-terminal region, putatively responsible for the formation of aggregate intermediates1,2. Though such mechanism has been proposed, the conformational and dynamical properties of the I26P monomer have not been experimentally determined yet.We use tryptophan triplet quenching by cystine to measure the rate of contact formation between the two ends of the I26P peptide. This technique has previously revealed conformational differences between rIAPP and hIAPP3. It allows detecting both changes in the equilibrium end-to-end distance distribution and in the diffusional dynamics of the end-to-end distance caused by fast reconfigurations of backbone dihedral angles. We compare results for I26P, hIAPP, rIAPP, and model worm like chain peptides of same length. We discuss the effect of proline substitutions on the conformation and dynamics of these intrinsically disordered proteins and their possible effect on amyloid aggregation.Footnotes1 Abedini A. et al. JACS 129 20072 Meng F. et al. JACS 132 20103 Vaiana SM et al. BiophysJ 97 2009