title: Alternative splicing creates two new architectures for human tyrosyl-tRNA synthetase.
abstract: Many human tRNA synthetases evolved alternative functions outside of protein synthesis. These functions are associated with over 200 splice variants (SVs), most of which are catalytic nulls that engender new biology. While known to regulate non-translational activities, little is known about structures resulting from natural internal ablations of any protein. Here, we report analysis of two closely related, internally deleted, SVs of homodimeric human tyrosyl-tRNA synthetase (TyrRS). In spite of both variants ablating a portion of the catalytic core and dimer-interface contacts of native TyrRS, each folded into a distinct stable structure. Biochemical and nuclear magnetic resonance (NMR) analysis showed that the internal deletion of TyrRSΔE2-4 SV gave an alternative, neomorphic dimer interface 'orthogonal' to that of native TyrRS. In contrast, the internal C-terminal splice site of TyrRSΔE2-3 prevented either dimerization interface from forming, and yielded a predominantly monomeric protein. Unlike ubiquitous TyrRS, the neomorphs showed clear tissue preferences, which were distinct from each other. The results demonstrate a sophisticated structural plasticity of a human tRNA synthetase for architectural reorganizations that are preferentially elicited in specific tissues.
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Departmentof Biology, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Pangu Biopharma, Edinburgh Tower, The landmark, 15 Queen'sRoad Central, Hong Kong, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Liu
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Pangu Biopharma, Edinburgh Tower, The landmark, 15 Queen'sRoad Central, Hong Kong, China.
authors.forename: Wing-Sze
authors.initials: WS
authors.lastname: Lo
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Pangu Biopharma, Edinburgh Tower, The landmark, 15 Queen'sRoad Central, Hong Kong, China.
authors.forename: Ching-Fun
authors.initials: CF
authors.lastname: Lau
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Pangu Biopharma, Edinburgh Tower, The landmark, 15 Queen'sRoad Central, Hong Kong, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Pangu Biopharma, Edinburgh Tower, The landmark, 15 Queen'sRoad Central, Hong Kong, China.
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zhou
authors.affiliation: aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China The Scripps Laboratories for tRNA Synthetase Research and the Departments of Chemical Physiology and of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Division of Life Science, State Key Laboratory of Molecular Neuroscience Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.affiliation: IAS HKUST - Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China The Scripps Laboratories for tRNA Synthetase Research and the Departments of Cell and Molecular Biology, and Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA The Scripps Laboratories for tRNA Synthetase Research and Departments of Metabolism & Aging, The Scripps Research Institute, Jupiter, FL 33458, USA schimmel@scripps.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D014448:Tyrosine-tRNA Ligase