title: Replacement of charged and polar residues in the coiled-coiled interface of huntingtin-interacting protein 1 (HIP1) causes aggregation and cell death.
abstract: HIP1 crystal structures solved in our laboratory revealed abnormalities in the coiled-coil region, suggesting intrinsic plasticity. To test this, specific amino acids in the coiled-coil were mutated. The apparent thermal stability of HIP1 was altered when Thr528 and Glu531 were replaced by leucine, and was enhanced when Lys510 was also mutated. In cells, HIP1 mutant expression produced aggregation. MTS and flow cytometry indicate a correlation between aggregated HIP1 and enhanced cell death. These data support the idea that flexibility of the HIP1 coiled-coil domain is important for normal function and may lead to new insights into Huntington's disease.
authors: Department of Molecular and Cellular Biochemistry, Indiana University Bloomington, Bloomington, IN 47405, United States.
authors: Sarah N
authors: SN
authors: Fontaine
authors: Scott P
authors: SP
authors: Bauer
authors: Xiaoyan
authors: X
authors: Lin
authors: Sara
authors: S
authors: Poorfarahani
authors: Joel A
authors: JA
authors: Ybe
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins