Huntingtin associates with acidic phospholipids at the plasma membrane.
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.
Kegel
Kimberly B
KB
Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. kegel@helix.mgh.harvard.edu
Sapp
Ellen
E
Yoder
Jennifer
J
Cuiffo
Benjamin
B
Sobin
Lindsay
L
Kim
Yun J
YJ
Qin
Zheng-Hong
ZH
Hayden
Michael R
MR
Aronin
Neil
N
Scott
David L
DL
Isenberg
Gerhard
G
Goldmann
Wolfgang H
WH
DiFiglia
Marian
M
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
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