title: Huntingtin associates with acidic phospholipids at the plasma membrane.
abstract: We have identified a domain in the N terminus of huntingtin that binds to membranes. A three-dimensional homology model of the structure of the binding domain predicts helical HEAT repeats, which emanate a positive electrostatic potential, consistent with a charge-based mechanism for membrane association. An amphipathic helix capable of inserting into pure lipid bilayers may serve to anchor huntingtin to the membrane. In cells, N-terminal huntingtin fragments targeted to regions of plasma membrane enriched in phosphatidylinositol 4,5-bisphosphate, receptor bound-transferrin, and endogenous huntingtin. N-terminal huntingtin fragments with an expanded polyglutamine tract aberrantly localized to intracellular regions instead of plasma membrane. Our data support a new model in which huntingtin directly binds membranes through electrostatic interactions with acidic phospholipids.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. kegel@helix.mgh.harvard.edu
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Kegel
authors.forename: Ellen
authors.initials: E
authors.lastname: Sapp
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yoder
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cuiffo
authors.forename: Lindsay
authors.initials: L
authors.lastname: Sobin
authors.forename: Yun J
authors.initials: YJ
authors.lastname: Kim
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Neil
authors.initials: N
authors.lastname: Aronin
authors.forename: David L
authors.initials: DL
authors.lastname: Scott
authors.forename: Gerhard
authors.initials: G
authors.lastname: Isenberg
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Goldmann
authors.forename: Marian
authors.initials: M
authors.lastname: DiFiglia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008051:Lipid Bilayers / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012984:Software; D055672:Static Electricity; D013347:Subcellular Fractions; D013696:Temperature; D014162:Transfection; D014168:Transferrin / Q000737:chemistry
chemical_list: D018076:DNA, Complementary; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008051:Lipid Bilayers; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D014168:Transferrin; C097188:polyglutamine; D005982:Glutathione Transferase