The Emerging Role of the First 17 Amino Acids of Huntingtin in Huntington's Disease

Overview

Journal Biomol Concepts

Specialty Biochemistry

Date 2015 Mar 6

PMID 25741791

Citations 27

Authors

James R Arndt

Maxmore Chaibva

Justin Legleiter

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is caused by a polyglutamine (polyQ) domain that is expanded beyond a critical threshold near the N-terminus of the huntingtin (htt) protein, directly leading to htt aggregation. While full-length htt is a large (on the order of ∼350 kDa) protein, it is proteolyzed into a variety of N-terminal fragments that accumulate in oligomers, fibrils, and larger aggregates. It is clear that polyQ length is a key determinant of htt aggregation and toxicity. However, the flanking sequences around the polyQ domain, such as the first 17 amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, influence other important biochemical properties of the protein and ultimately its role in pathogenesis. Here, we review the impact of Nt17 on htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of posttranslational modifications (PTMs) that occur in Nt17 in HD, and the function of Nt17 as a membrane targeting domain.

Citing Articles

Structure Characterization of a Disordered Peptide Using In-Droplet Hydrogen/Deuterium Exchange Mass Spectrometry and Molecular Dynamics.

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Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.

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Binding structures of SERF1a with NT17-polyQ peptides of huntingtin exon 1 revealed by SEC-SWAXS, NMR and molecular simulation.

Lin T, Shih O, Tsai T, Yeh Y, Liao K, Mansel B IUCrJ. 2024; 11(Pt 5):849-858.

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Charge within Nt17 peptides modulates huntingtin aggregation and initial lipid binding events.

Stonebraker A, Hankin R, Kapp K, Li P, Valentine S, Legleiter J Biophys Chem. 2023; 303:107123.

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Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation.

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