title: Human tRNA synthetase catalytic nulls with diverse functions.
abstract: Genetic efficiency in higher organisms depends on mechanisms to create multiple functions from single genes. To investigate this question for an enzyme family, we chose aminoacyl tRNA synthetases (AARSs). They are exceptional in their progressive and accretive proliferation of noncatalytic domains as the Tree of Life is ascended. Here we report discovery of a large number of natural catalytic nulls (CNs) for each human AARS. Splicing events retain noncatalytic domains while ablating the catalytic domain to create CNs with diverse functions. Each synthetase is converted into several new signaling proteins with biological activities "orthogonal" to that of the catalytic parent. We suggest that splice variants with nonenzymatic functions may be more general, as evidenced by recent findings of other catalytically inactive splice-variant enzymes.
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's Road Central, Hong Kong, China.
authors.forename: Wing-Sze
authors.initials: WS
authors.lastname: Lo
authors.affiliation: The Scripps Laboratories for tRNA Synthetase Research, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA. aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gardiner
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's Road Central, Hong Kong, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Xu
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's Road 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's Road 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's Road 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: John D
authors.initials: JD
authors.lastname: Mendlein
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: aTyr Pharma, 3545 John Hopkins Court, Suite 250, San Diego, CA 92121, USA.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
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, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kin-Fai
authors.initials: KF
authors.lastname: Au
authors.affiliation: Department of Statistics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Wing Hung
authors.initials: WH
authors.lastname: Wong
authors.affiliation: The Scripps Laboratories for tRNA Synthetase Research, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
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, The Scripps Research Institute, 10650 North Torrey Pines Road, La Jolla, CA 92037, USA. The Scripps Laboratories for tRNA Synthetase Research, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA. schimmel@scripps.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D017398:Alternative Splicing; D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D020134:Catalytic Domain; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D020033:Protein Isoforms; D011994:Recombinant Proteins; D000604:Amino Acyl-tRNA Synthetases