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Does N-terminal huntingtin function as a 'holdase' for inhibiting cellular protein aggregation?
Ratnika Sethi1, Neha Tripathi2, Anusha R Pallapati1
1Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
The FEBS Journal
|April 10, 2018
Summary
Wild-type huntingtin exon1 N17 domain acts as a novel protein stabilizer, inhibiting aggregation in vitro and in yeast. This finding offers new insights into Huntington
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Huntington's disease (HD) pathogenesis involves truncated mutant huntingtin.
- The function of N-terminal wild-type huntingtin fragments is less understood.
- A yeast model for HD is utilized, featuring specific modifications to huntingtin exon1.
Purpose of the Study:
- To investigate the function of the N-terminal wild-type huntingtin sequence.
- To explore the protein's role in inhibiting aggregation.
- To identify the specific domain responsible for this function.
Main Methods:
- In vitro protein aggregation assays.
- Yeast cell-based experiments.
- Mutagenesis studies (deletion and point mutation L4A).
Main Results:
- Wild-type huntingtin exon1 sequence inhibits protein aggregation in vitro and in yeast.
- The N17 domain stabilizes client proteins (luciferase, α-synuclein, p53) in a soluble, non-native state, mimicking holdase activity.
- N17 domain helical conformation is crucial for this stabilizing function and for mutant huntingtin aggregation.
Conclusions:
- The N17 domain of wild-type huntingtin exon1 possesses a novel 'holdase' like function, stabilizing client proteins and preventing aggregation.
- This amphipathic helix plays a critical role in protein homeostasis and is implicated in Huntington's disease pathogenesis.
- Findings suggest a new therapeutic target for Huntington's disease by modulating N17 domain function.