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.

Unraveling the Puzzle of Therapeutic Peptides: A Promising Frontier in Huntington’s Disease Treatment

“…By incorporating this structural feature, QBP1 and mQBP1 can exert their inhibitory effects on HDx1 aggregation. 112 In specific cases, it has been observed that QBP1 and mQBP1 can retain their inhibitory activity even when the PG motif is replaced with other β-turn supporting residues. For example, variants such as QBP1-pG, QBP1-UG, and QBP1-NG, where the PG motif is substituted with alternative residues that support β-turn conformation, maintain their activity in inhibiting Trx-HDx1 aggregation.…”

“…The inability of QBP1-PP to inhibit aggregation further highlights the importance of the specific structural elements and residues in QBP1 and mQBP1 for their functional effectiveness in preventing protein aggregation (Figure 10). 112 There are three methods for delivering QBP1 to the affected neurons in the brain (Figures 11, 12, and 13):…”

“…The β-turn motif provided by the PG dipeptide likely contributes to the overall folding and conformational stability of QBP1 and mQBP1, allowing them to interact with and disrupt the aggregation process of HDx1. By incorporating this structural feature, QBP1 and mQBP1 can exert their inhibitory effects on HDx1 aggregation . In specific cases, it has been observed that QBP1 and mQBP1 can retain their inhibitory activity even when the PG motif is replaced with other β-turn supporting residues.…”

In silico designing of putative peptides for targeting pathological protein Htt in Huntington's disease

“…The p42 binds on 480 residues to 502 residues while QBP 1 binds on other sites in N terminal region of Htt protein. Herein, we have compared peptide-based (ED 11, Exendin-4, CaM, QBP1, BIP) therapeutic approach for targeting the aggregate prone areas in Htt protein, that can decelerate the progression of disease [ 12 , 13 , 14 ]. QBP1 and p42 targets poly Q disease, ED11 targets caspase 6 but is used in Huntington's therapy.…”