The β-turn-supporting motif in the polyglutamine binding peptide QBP1 is essential for inhibiting huntingtin aggregation

Abstract

Aggregation of polyglutamine proteins is a hallmark of several neurodegenerative diseases. The 11-residue polyglutamine binding peptide Ac-SNWKWWPGIFD-am, known as QBP1, inhibits polyglutamine aggregation. Besides, a minimal 8-residue stretch in the QBP1 peptide (Ac-WKWWPGIF-am) is reported in the literature to retain this activity. Both peptides harbor a Pro-Gly dipeptide motif, a feature characteristic of potential β-turn regions. Here, we investigated whether the presence of this β-turn motif is necessary for the inhibition of huntingtin aggregation, a polyglutamine protein implicated in Huntington’s disease. Using single amino acid substitutions to generate analogs that could support, introduce, or eliminate the β-turn, we show that the turn-supporting motif is essential for QBP1-mediated inhibition of huntingtin aggregation.