Huntingtin Associates with Acidic Phospholipids at the Plasma Membrane

• Published in: The Journal of biological chemistry Vol. 280; no. 43; pp. 36464 - 36473
• Main Authors: Kegel, Kimberly B., Sapp, Ellen, Yoder, Jennifer, Cuiffo, Benjamin, Sobin, Lindsay, Kim, Yun J., Qin, Zheng-Hong, Hayden, Michael R., Aronin, Neil, Scott, David L., Isenberg, Gerhard, Goldmann, Wolfgang H., DiFiglia, Marian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.10.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Amino Acid Sequence; Animals; Blotting, Western; Calorimetry, Differential Scanning; Cell Line, Tumor; Cell Membrane - metabolism; Chlorocebus aethiops; COS Cells; DNA, Complementary - metabolism; Endoplasmic Reticulum - metabolism; Glutathione Transferase - metabolism; Humans; Huntingtin Protein; Immunohistochemistry; Immunoprecipitation; Lipid Bilayers - chemistry; Microscopy, Fluorescence; Models, Molecular; Molecular Sequence Data; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - physiology; Nuclear Proteins - chemistry; Nuclear Proteins - physiology; Peptides - chemistry; Phosphatidylinositol 4,5-Diphosphate - chemistry; Phospholipids - chemistry; Protein Binding; Protein Structure, Tertiary; Recombinant Fusion Proteins - metabolism; Software; Static Electricity; Subcellular Fractions; Temperature; Transfection; Transferrin - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M503672200

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.