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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Blotting, Western
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COS Cells
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Calorimetry, Differential Scanning
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Cell Line, Tumor
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Cell Membrane / metabolism*
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Chlorocebus aethiops
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DNA, Complementary / metabolism
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Endoplasmic Reticulum / metabolism
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Glutathione Transferase / metabolism
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Humans
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Huntingtin Protein
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Immunohistochemistry
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Immunoprecipitation
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Lipid Bilayers / chemistry
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Microscopy, Fluorescence
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / physiology*
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Nuclear Proteins / chemistry
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Nuclear Proteins / physiology*
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Peptides / chemistry
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Phosphatidylinositol 4,5-Diphosphate / chemistry
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Phospholipids / chemistry*
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Protein Binding
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / metabolism
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Software
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Static Electricity
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Subcellular Fractions
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Temperature
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Transfection
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Transferrin / chemistry
Substances
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DNA, Complementary
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HTT protein, human
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Huntingtin Protein
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Lipid Bilayers
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Phosphatidylinositol 4,5-Diphosphate
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Phospholipids
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Recombinant Fusion Proteins
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Transferrin
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polyglutamine
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Glutathione Transferase
Associated data
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GENBANK/AAC63983
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GENBANK/BAA36752
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GENBANK/P42859
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GENBANK/P51111
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RefSeq/NP_002102