Possible Co-Evolution of Polyglutamine and Polyproline in Huntingtin Protein: Proline-Rich Domain as Transient Folding Chaperone.

Abstract

Huntington's disease is an inherited neurodegenerative disorder caused by the overduplication of CAG repeats in the Huntingtin gene. Recent findings revealed that among the orthologs, the expansion of CAG repeats (polyQ) in the Huntingtin gene occurs in tandem with the duplication of CCG repeats (polyP). However, the molecular mechanism of this possible co-evolution remains unknown. We examined the structures of Huntingtin exon 1 (HttEx1) from six species along with five designed mutants. We found that the polyP segments "chaperone" the rest of the HttEx1 by forming ad hoc polyP binding grooves. Such a process elongates the otherwise poorly solvated polyQ domain, while modulating its secondary structure propensity from β-strands to α-helices. This chaperoning effect is achieved mostly through transient hydrogen bond interactions between polyP and the rest of HttEx1, resulting in a striking golden ratio of ∼2:1 between the chain lengths of polyQ and polyP.