Asparagine Repeat Peptides: Aggregation Kinetics and Comparison with Glutamine Repeats.

Abstract

Amino acid repeat runs are common occurrences in eukaryotic proteins, with glutamine (Q) and asparagine (N) as particularly frequent repeats. Abnormal expansion of Q-repeat domains causes at least nine neurodegenerative disorders, most likely because expansion leads to protein misfolding, aggregation, and toxicity. The linkage between Q-repeats and disease has motivated several investigations into the mechanism of aggregation and the role of Q-repeat length in aggregation. Curiously, glutamine repeats are common in vertebrates, whereas N-repeats are virtually absent in vertebrates, but common in invertebrates. One hypothesis for the lack of N-repeats in vertebrates is biophysical; that is, there is strong selective pressure in higher organisms against aggregation-prone proteins. If true, then asparagine and glutamine repeats must differ substantially in their aggregation properties despite their chemical similarities. In this work, aggregation of peptides with asparagine repeats of variable length (12-24) were characterized and compared to that of similar peptides with glutamine repeats. As with glutamine, aggregation of N-repeat peptides was strongly length-dependent. Replacement of glutamine with asparagine caused a subtle shift in the conformation of the monomer, which strongly affected the rate of aggregation. Specifically, N-repeat peptides adopted β-turn structural elements, leading to faster self-assembly into globular oligomers and much more rapid conversion into fibrillar aggregates, compared to Q-repeat peptides. These biophysical differences may account for the differing biological roles of N- versus Q-repeat domains.