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While the role of truncated mutant huntingtin is described in Huntington's disease (<jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content>) pathogenesis, the function of N\u2010terminal wild\u2010type protein is less studied. The yeast model of <jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content> is generated by the presence of <jats:styled-content style=\"fixed-case\">FLAG<\/jats:styled-content> tag and absence of polyproline tract as flanking sequences of the elongated polyglutamine stretch. We show that the same sequence derived from wild\u2010type huntingtin exon1 is able to inhibit the aggregation of proteins <jats:italic>in vitro<\/jats:italic> and in yeast cells. It is able to stabilize client proteins as varied as luciferase, \u03b1\u2010synuclein, and p53 in a soluble but non\u2010native state. This is somewhat similar to the \u2018holdase\u2019 function of small heat shock proteins and \u2018nonchaperone proteins\u2019 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\u2010terminal mutant protein. Our results provide evidence for a novel function for the amphipathic helix derived from exon1 of wild\u2010type huntingtin.<\/jats:p>","DOI":"10.1111\/febs.14457","type":"journal-article","created":{"date-parts":[[2018,4,9]],"date-time":"2018-04-09T20:47:44Z","timestamp":1523306864000},"page":"1791-1811","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Does N\u2010terminal huntingtin function as a \u2018holdase\u2019 for inhibiting cellular protein aggregation?"],"prefix":"10.1111","volume":"285","author":[{"given":"Ratnika","family":"Sethi","sequence":"first","affiliation":[{"name":"Department of Biotechnology National Institute of Pharmaceutical Education and Research Punjab India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neha","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Pharmacoinformatics National Institute of Pharmaceutical Education and Research 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