title: HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.
abstract: Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington disease. This mutation influences the interaction of huntingtin with different proteins, including huntingtin-interacting protein 1 (HIP1), in which affinity to bind to mutant huntingtin is profoundly reduced. Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276-335. This region, which contains consensus clathrin- and AP2-binding sites, functions in conjunction with the coiled-coil domain to target HIP1 to CCVs. Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Metzler
authors.forename: V
authors.initials: V
authors.lastname: Legendre-Guillemin
authors.forename: L
authors.initials: L
authors.lastname: Gan
authors.forename: V
authors.initials: V
authors.lastname: Chopra
authors.forename: A
authors.initials: A
authors.lastname: Kwok
authors.forename: P S
authors.initials: PS
authors.lastname: McPherson
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D033962:Adaptor Protein Complex 2; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology*; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D004705:Endocytosis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014168:Transferrin / Q000493:pharmacokinetics
chemical_list: D033962:Adaptor Protein Complex 2; D033942:Adaptor Proteins, Vesicular Transport; D000596:Amino Acids; D002352:Carrier Proteins; D002966:Clathrin; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; D008565:Membrane Proteins; D014168:Transferrin; D004247:DNA