title: Structural insights into the specific binding of huntingtin proline-rich region with the SH3 and WW domains.
abstract: The interactions of huntingtin (Htt) with the SH3 domain- or WW domain-containing proteins have been implicated in the pathogenesis of Huntington's disease (HD). We report the specific interactions of Htt proline-rich region (PRR) with the SH3GL3-SH3 domain and HYPA-WW1-2 domain pair by NMR. The results show that Htt PRR binds with the SH3 domain through nearly its entire chain, and that the binding region on the domain includes the canonical PxxP-binding site and the specificity pocket. The C terminus of PRR orients to the specificity pocket, whereas the N terminus orients to the PxxP-binding site. Htt PRR can also specifically bind to WW1-2; the N-terminal portion preferentially binds to WW1, while the C-terminal portion binds to WW2. This study provides structural insights into the specific interactions between Htt PRR and its binding partners as well as the alteration of these interactions that involve PRR, which may have implications for the understanding of HD.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Gao
authors.forename: Xian-Zhong
authors.initials: XZ
authors.lastname: Yan
authors.forename: Ai-Xin
authors.initials: AX
authors.lastname: Song
authors.forename: Yong-Gang
authors.initials: YG
authors.lastname: Chang
authors.forename: Xue-Chao
authors.initials: XC
authors.lastname: Gao
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Hu
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D000071058:Huntingtin Protein; D021621:Imaging, Three-Dimensional; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000502:physiology*; D010455:Peptides / Q000737:chemistry; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013113:Spin Labels; D018909:src Homology Domains
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D013113:Spin Labels; D011392:Proline