The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease

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 huningtin (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 polyQ domain, such as the first seventeen amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, other important biochemical properties of the protein, and ultimately it role in pathogenesis. Here, we review the impact of Nt17 on both htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of post translational modifications (PTMs) that occur in Nt17 in HD, and Nt17’s function as a membrane targeting domain.

Inhibition of polyglutamine aggregation by SIMILAR huntingtin N‐terminal sequences: Prospective molecules for preclinical evaluation in Huntington's disease

“…In this study, a similar effect was observed upon coincubating it with NT 17 Q 35 P 10 K 2 peptide (Figure D–F), reaffirming its inhibitory property. This effect is due to the ability of Hum‐ NT 17 to form an amphipathic α‐helix with a strong hydrophobic core toward one side during its interaction with the NT 17 segment of NT 17 Q 35 P 10 K 2 . The Schiffer and Edmundson helical wheel representation, where the hydrophobic core of Hum‐ NT 17 was oriented exactly similar to that of the NT 17 segment of NT 17 Q 35 P 10 K 2 , might resemble this phenomenon (Figure ).…”

“…This brings the polyGln chains closer in space, enhances its local concentration, and thus improves the efficiency of amyloid nucleation. Further monomer addition on to the postulated nuclei results in fibril‐elongation and amyloid‐rich aggregate formation …”

Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease

“…157, 220, 226, 227 Here, we will focus on PTMs that occur within the N17 domain of htt, as several of these impact polyQ structure and aggregation. 228 Several PTMs occur in this domain – i.e., phosphorylation, 229–232 acetylation, 233 ubiquitination, 234 SUMOylation, 235, 236 palmitoylation, 237 oxidation, 238 and transglutamination. 239 Additionally, the initiator methionine of N17 can be proteolytically removed, and this may occur rapidly after or during synthesis.…”

Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation‐Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6

“…[1] This, combined with the fact that this short N-terminal sequence harbors several residues that are subjected to diverse posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination and sumoylation (Scheme S1-A in the Supporting Information), suggests that PTMs may serve as reversible molecular switches for regulating Htt structure, interactome, cellular properties and toxicity. [2] However, the lack of knowledge about the enzymes involved in regulating these modifications has made it difficult to decipher their role in regulating the function(s) of Htt in health and disease.…”