The N17 domain of huntingtin as a multifaceted player in Huntington's disease

Abstract

Huntington's disease (HD) is primarily caused by the aberrant aggregation of the N-terminal exon 1 fragment of mutant huntingtin protein (mHttex1) with expanded polyglutamine (polyQ) repeats in neurons. The first 17 amino acids of the N-terminus of Httex1 (N17 domain) immediately preceding the polyQ repeat domain are evolutionarily conserved across vertebrates and play multifaceted roles in the pathogenesis of HD. Due to its amphipathic helical properties, the N17 domain, both alone and when membrane-associated, promotes mHttEx1 aggregation. Diverse post-translational modifications (PTMs) in the N17 domain alter the aggregation state, thus modulating the cellular toxicity of mHttex1. Furthermore, the N17 domain serves as a nuclear export signal (NES) and mediates the cytoplasmic localization of mHttex1. This review summarizes the four main roles of the N17 domain in regulating HD pathology and discusses potential therapeutic approaches targeting this N17 domain to mitigate HD progression.

Keywords: Huntingtin; Huntington’s disease; N17 domain; aggregation; post-translational modification (PTM).

FIGURE 1

Sequences and amphipathic helical property of the N17 domain of Httex1 (A) Sequence alignment of the N17 domain of Httex1. Httex1 is composed of three main domains: N17 domain, polyQ repeat domain, and proline-rich domain (PRD). The sequences of the N17 domain are highly conserved among tested species (Atwal et al., 2007). (B) The helical wheel illustrates the distribution of hydrophobic and hydrophilic amino acids in the amphipathic helix of the N17 domain.

FIGURE 2

Multi-functional roles of the N17 domain in modulating aggregation and cellular localization of mHttex1. As an aggregation-promoting motif, the hydrophobic residues (highlighted in magenta) in the N17 domain (light pink) form a core hydrophobic interface that may further stabilize polyQ aggregation. The amphipathic N17 domain also interacts with the lipid bilayers, thereby enhancing the local concentration and aggregation of mHttex1. Hydrophobic (magenta) and charged (blue) residues in the N17 domain are located on the interior and exterior surfaces of the membrane, respectively. Three types of PTMs (phosphorylation, acetylation, and SUMOylation) in the N17 domain are known to alter the aggregation state of mHttex1. Furthermore, the N17 domain contains NES-like consensus sequences, ФX_(2–3) ФX_(2–3)ФXФ, where Ф and X are hydrophobic amino acids (highlighted in red) and random amino acids, respectively. In the absence of the N17 domain, toxic mHttex1 aggregates accumulate in the nucleus.