title: Chaperone protein HYPK interacts with the first 17 amino acid region of Huntingtin and modulates mutant HTT-mediated aggregation and cytotoxicity.
abstract: Huntington's disease is a polyglutamine expansion disorder, characterized by mutant HTT-mediated aggregate formation and cytotoxicity. Many reports suggests roles of N-terminal 17 amino acid domain of HTT (HTT-N17) towards subcellular localization, aggregate formation and subsequent pathogenicity induced by N-terminal HTT harboring polyQ stretch in pathogenic range. HYPK is a HTT-interacting chaperone which can reduce N-terminal mutant HTT-mediated aggregate formation and cytotoxicity in neuronal cell lines. However, how HYPK interacts with N-terminal fragment of HTT remained unknown. Here we report that specific interaction of HYPK with HTT-N17 is crucial for the chaperone activity of HYPK. Deletion of HTT-N17 leads to formation of tinier, SDS-soluble nuclear aggregates formed by N-terminal mutant HTT. The increased cytotoxicity imparted by these tiny aggregates might be contributed due to loss of interaction with HYPK.
authors.affiliation: Crystallography & Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India; Centre for Neuroscience, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Kamalika Roy
authors.initials: KR
authors.lastname: Choudhury
authors.affiliation: Biomedical Genomics Centre, PG Polyclinic Building, 5, Suburbun Hospital Road, Kolkata 700020, India. Electronic address: nitai_sinp@yahoo.com.
authors.forename: Nitai P
authors.initials: NP
authors.lastname: Bhattacharyya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010455:Peptides; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D002352:Carrier Proteins; C086055:HTT protein, human; C581869:HYPK protein, mouse; D000071058:Huntingtin Protein; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine
keywords: Aggregate; Cytotoxicity; HTT-N17; HYPK; Huntington’s disease