title: Structural basis of the phosphorylation dependent complex formation of neurodegenerative disease protein Ataxin-1 and RBM17.
abstract: Spinocerebellar Ataxia Type1 (SCA1) is a dominantly inherited neurodegenerative disease and belongs to polyglutamine expansion disorders. The polyglutamine expansion in Ataxin-1 (ATXN1) is responsible for SCA1 pathology. ATXN1 forms at least two distinct complexes with Capicua (CIC) or RNA-binding motif protein 17 (RBM17). The wild-type ATXN1 dominantly forms a complex with CIC and the polyglutamine expanded form of ATXN1 favors to form a complex with RBM17. The phosphorylation of Ser776 in ATXN1 is critical for SCA1 pathology and serves as a binding platform for RBM17. However, the molecular basis of the phospho-specific binging of ATXN1 to RBM17 is not delineated. Here, we present the modeled structure of RBM17 bound to the phosphorylated ATXN1 peptide. The structure reveals the phosphorylation specific interaction between ATXN1 and RBM17 through a salt-bridge network. Furthermore, the modeled structure and the interactions between RBM17 and ATXN1 were validated through mutagenesis study followed by Surface Plasmon Resonance binding experiments. This work delineates the molecular basis of the interaction between RBM17 and the phosphorylated form of ATXN1, which is critical for SCA1 pathology. Furthermore, the structure of RBM17 and pATXN1 peptide might be utilized to target RBM17-ATXN1 interaction to modulate SCA1 pathogenesis.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Kim
authors.affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea.
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea. Electronic address: sunchoi@ewha.ac.kr.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: songj@kaist.ac.kr.
authors.forename: Ji-Joon
authors.initials: JJ
authors.lastname: Song
mesh_terms: D000067696:Ataxin-1; D000067528:Ataxins; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009687:Nuclear Proteins / Q000737:chemistry*; D010766:Phosphorylation; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry; D020754:Spinocerebellar Ataxias / Q000473:pathology; D020349:Surface Plasmon Resonance
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C498610:CIC protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C121693:RBM17 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins
keywords: Interaction; Neurodegenerative disease; Phosphorylation; Spinocerebellar Ataxia Type1 (SCA1); Structure modeling