title: Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity.
abstract: Huntingtin (Htt) is a widely expressed protein that causes tissue-specific degeneration when mutated to contain an expanded polyglutamine (poly(Q)) domain. Although Htt is large, 350 kDa, the appearance of amino-terminal fragments of Htt in extracts of postmortem brain tissue from patients with Huntington disease (HD), and the fact that an amino-terminal fragment, Htt exon 1 protein (Httex1p), is sufficient to cause disease in models of HD, points to the importance of the amino-terminal region of Htt in the disease process. The first exon of Htt encodes 17 amino acids followed by a poly(Q) repeat of variable length and culminating with a proline-rich domain of 50 amino acids. Because modifications to this fragment have the potential to directly affect pathogenesis in several ways, we have surveyed this fragment for potential post-translational modifications that might affect Htt behavior and detected several modifications of Httex1p. Here we report that the most prevalent modifications of Httex1p are NH(2)-terminal acetylation and phosphorylation of threonine 3 (pThr-3). We demonstrate that pThr-3 occurs on full-length Htt in vivo, and that this modification affects the aggregation and pathogenic properties of Htt. Thus, therapeutic strategies that modulate these events could in turn affect Htt pathogenesis.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
authors.forename: Charity T
authors.initials: CT
authors.lastname: Aiken
authors.forename: Joan S
authors.initials: JS
authors.lastname: Steffan
authors.forename: Cortnie M
authors.initials: CM
authors.lastname: Guerrero
authors.forename: Hasan
authors.initials: H
authors.lastname: Khashwji
authors.forename: Tamas
authors.initials: T
authors.lastname: Lukacsovich
authors.forename: Danielle
authors.initials: D
authors.lastname: Simmons
authors.forename: Judy M
authors.initials: JM
authors.lastname: Purcell
authors.forename: Kimia
authors.initials: K
authors.lastname: Menhaji
authors.forename: Ya-Zhen
authors.initials: YZ
authors.lastname: Zhu
authors.forename: Kim
authors.initials: K
authors.lastname: Green
authors.forename: Frank
authors.initials: F
authors.lastname: Laferla
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Leslie Michels
authors.initials: LM
authors.lastname: Thompson
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
mesh_terms: D000107:Acetylation; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D013912:Threonine