Does N‐terminal huntingtin function as a ‘holdase’ for inhibiting cellular protein aggregation?

Sethi, Ratnika ; Tripathi, Neha ; Pallapati, Anusha R. ; Gaikar, Abhishek ; Bharatam, Prasad V. ; Roy, Ipsita (2018) Does N‐terminal huntingtin function as a ‘holdase’ for inhibiting cellular protein aggregation? The FEBS Journal, 285 (10). pp. 1791-1811. ISSN 1742-464X

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Official URL: http://doi.org/10.1111/febs.14457

Related URL: http://dx.doi.org/10.1111/febs.14457

Abstract

Proteolytic cleavage of huntingtin gives rise to N-terminal fragments. While the role of truncated mutant huntingtin is described in Huntington's disease (HD) pathogenesis, the function of N-terminal wild-type protein is less studied. The yeast model of HD is generated by the presence of FLAG tag and absence of polyproline tract as flanking sequences of the elongated polyglutamine stretch. We show that the same sequence derived from wild-type huntingtin exon1 is able to inhibit the aggregation of proteins in vitro and in yeast cells. It is able to stabilize client proteins as varied as luciferase, α-synuclein, and p53 in a soluble but non-native state. This is somewhat similar to the 'holdase' function of small heat shock proteins and 'nonchaperone proteins' which are able to stabilize partially unfolded client proteins in a nonspecific manner, slowing down their aggregation. Mutagenesis studies show this property to be localized at the N17 domain preceding the polyglutamine tract. Distortion of this ordered segment, either by deletion of this segment or mutation of a single residue (L4A), leads to decreased stability and increased aggregation of client proteins. It is interesting to note that the helical conformation of the N17 domain is also essential for aggregation of the N-terminal mutant protein. Our results provide evidence for a novel function for the amphipathic helix derived from exon1 of wild-type huntingtin.

Item Type:Article
Source:Copyright of this article belongs to FOIA Privacy.
Keywords:N17 Domain; Amphipathic Helix; Holdase; Huntingtin; Yeast Model.
ID Code:116308
Deposited On:12 Apr 2021 09:22
Last Modified:12 Apr 2021 09:22

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