Expansion of polyglutamine (polyQ) tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35–40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel β-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the β-helices observed in simulations, all residues adopt β-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 ± 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel β-hairpins in their ground state, in agreement with experiments. The lower stability of mutant β-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation.
Nine human diseases, including Huntington's disease, are associated with an expanded trinucleotide sequence CAG in genes. Since CAG codes for the amino acid glutamine, these disorders are collectively known as polyglutamine diseases. Although the genes (and proteins) involved in different polyglutamine diseases have little in common, the disorders they cause follow a strikingly similar course: If the length of the expansion exceeds a critical value of 35–40, the greater the number of glutamine repeats in a protein, the earlier the onset of disease and the more severe the symptoms. This fact suggests that abnormally long glutamine tracts render their host protein toxic to nerve cells, and all polyglutamine diseases are hypothesized to progress via common molecular mechanisms. One possible mechanism of cell death is that the abnormally long sequence of glutamines acquires a shape that prevents the host protein from folding into its proper shape. What is the structure acquired by polyglutamine and what is the molecular basis of the observed threshold repeat length? Using computer models of polyglutamine, the authors show that if, and only if, the length of polyglutamine repeats is longer than the critical value found in disease, it acquires a specific shape called a β-helix. The longer the glutamine tract length, the higher is the propensity to form β-helices. This length-dependent formation of β-helices by polyglutamine stretches may provide a unified molecular framework for understanding the structural basis of different trinucleotide repeat-associated diseases.