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.

[1]  H. Dohlman,et al.  Differential Regulation of G Protein α Subunit Trafficking by Mono- and Polyubiquitination* , 2005, Journal of Biological Chemistry.

[2]  Lawrence M. Lifshitz,et al.  Phosphatidylinositol-4,5-Bisphosphate-Rich Plasma Membrane Patches Organize Active Zones of Endocytosis and Ruffling in Cultured Adipocytes , 2004, Molecular and Cellular Biology.

[3]  P. De Camilli,et al.  Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Saint-Dic,et al.  HIP1 and HIP1r Stabilize Receptor Tyrosine Kinases and Bind 3-Phosphoinositides via Epsin N-terminal Homology Domains*[boxs] , 2004, Journal of Biological Chemistry.

[5]  L. Thompson,et al.  Autophagy regulates the processing of amino terminal huntingtin fragments. , 2003, Human molecular genetics.

[6]  D. Morrison,et al.  Regulation of MAP kinase signaling modules by scaffold proteins in mammals. , 2003, Annual review of cell and developmental biology.

[7]  Scott T. Brady,et al.  Neuropathogenic Forms of Huntingtin and Androgen Receptor Inhibit Fast Axonal Transport , 2003, Neuron.

[8]  M. Roth,et al.  Phosphatidylinositol phosphate 5-kinase Iβ recruits AP-2 to the plasma membrane and regulates rates of constitutive endocytosis , 2003, The Journal of cell biology.

[9]  Erich E Wanker,et al.  The hunt for huntingtin function: interaction partners tell many different stories. , 2003, Trends in biochemical sciences.

[10]  Manuel C. Peitsch,et al.  SWISS-MODEL: an automated protein homology-modeling server , 2003, Nucleic Acids Res..

[11]  M. Lemmon,et al.  Phosphoinositide Recognition Domains , 2003, Traffic.

[12]  Y. Hannun,et al.  Structural Requirements for Selective Binding of ISC1to Anionic Phospholipids* , 2002, The Journal of Biological Chemistry.

[13]  J. Nevins,et al.  Huntingtin Is Present in the Nucleus, Interacts with the Transcriptional Corepressor C-terminal Binding Protein, and Represses Transcription* , 2002, The Journal of Biological Chemistry.

[14]  L. Traub,et al.  Clathrin- and AP-2-binding Sites in HIP1 Uncover a General Assembly Role for Endocytic Accessory Proteins* , 2001, The Journal of Biological Chemistry.

[15]  Z. Qin,et al.  Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  V. Niggli,et al.  Structural properties of lipid-binding sites in cytoskeletal proteins. , 2001, Trends in biochemical sciences.

[17]  H. Lehrach,et al.  The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis. , 2001, Human molecular genetics.

[18]  F. Quiocho,et al.  A Novel All Helix Fold of the AP180 Amino-Terminal Domain for Phosphoinositide Binding and Clathrin Assembly in Synaptic Vesicle Endocytosis , 2001, Cell.

[19]  M. DiFiglia,et al.  Huntingtin Expression Stimulates Endosomal–Lysosomal Activity, Endosome Tubulation, and Autophagy , 2000, The Journal of Neuroscience.

[20]  Pico Caroni,et al.  Gap43, Marcks, and Cap23 Modulate Pi(4,5p)2 at Plasmalemmal Rafts, and Regulate Cell Cortex Actin Dynamics through a Common Mechanism , 2000, The Journal of cell biology.

[21]  A. Seelig,et al.  Phospholipid Binding of Synthetic Talin Peptides Provides Evidence for an Intrinsic Membrane Anchor of Talin* , 2000, The Journal of Biological Chemistry.

[22]  P. De Camilli,et al.  Epsin 1 Undergoes Nucleocytosolic Shuttling and Its Eps15 Interactor Nh2-Terminal Homology (Enth) Domain, Structurally Similar to Armadillo and Heat Repeats, Interacts with the Transcription Factor Promyelocytic Leukemia Zn2+ Finger Protein (Plzf) , 2000, The Journal of cell biology.

[23]  I. Gaidarov,et al.  Phosphoinositide–Ap-2 Interactions Required for Targeting to Plasma Membrane Clathrin-Coated Pits , 1999, The Journal of cell biology.

[24]  L Hennig,et al.  WinGene/WinPep: user-friendly software for the analysis of amino acid sequences. , 1999, BioTechniques.

[25]  D. Tagle,et al.  Mutant Huntingtin Expression in Clonal Striatal Cells: Dissociation of Inclusion Formation and Neuronal Survival by Caspase Inhibition , 1999, The Journal of Neuroscience.

[26]  Brian A. Hemmings,et al.  The Structure of the Protein Phosphatase 2A PR65/A Subunit Reveals the Conformation of Its 15 Tandemly Repeated HEAT Motifs , 1999, Cell.

[27]  Imara Y. Perera,et al.  A Phosphatidylinositol 4-Kinase Pleckstrin Homology Domain That Binds Phosphatidylinositol 4-Monophosphate* , 1998, The Journal of Biological Chemistry.

[28]  C. Schwarz,et al.  Wild-Type and Mutant Huntingtins Function in Vesicle Trafficking in the Secretory and Endocytic Pathways , 1998, Experimental Neurology.

[29]  Péter Várnai,et al.  Visualization of Phosphoinositides That Bind Pleckstrin Homology Domains: Calcium- and Agonist-induced Dynamic Changes and Relationship to Myo-[3H]inositol-labeled Phosphoinositide Pools , 1998, The Journal of cell biology.

[30]  I. Kanazawa,et al.  HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain , 1997, Nature Genetics.

[31]  H. Lehrach,et al.  HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. , 1997, Human molecular genetics.

[32]  A. Muga,et al.  Binding of Molten Globule-like Conformations to Lipid Bilayers , 1995, The Journal of Biological Chemistry.

[33]  Peer Bork,et al.  HEAT repeats in the Huntington's disease protein , 1995, Nature Genetics.

[34]  W. Goldmann,et al.  Interaction of the 47-kDa talin fragment and the 32-kDa vinculin fragment with acidic phospholipids: a computer analysis. , 1995, Biophysical journal.

[35]  Christopher A Ross,et al.  Widespread expression of Huntington's disease gene (IT15) protein product , 1995, Neuron.

[36]  R. Carraway,et al.  Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons , 1995, Neuron.

[37]  M. Ehrlich,et al.  Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[38]  W. Goldmann,et al.  Insertion of filamin into lipid membranes examined by calorimetry, the film balance technique, and lipid photolabeling. , 1994, Biochemistry.

[39]  N. Guex,et al.  SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling , 1997, Electrophoresis.