title: Internally deleted human tRNA synthetase suggests evolutionary pressure for repurposing.
abstract: Aminoacyl-tRNA synthetases (AARSs) catalyze aminoacylation of tRNAs in the cytoplasm. Surprisingly, AARSs also have critical extracellular and nuclear functions. Evolutionary pressure for new functions might be manifested by splice variants that skip only an internal catalytic domain (CD) and link noncatalytic N- and C-terminal polypeptides. Using disease-associated histidyl-tRNA synthetase (HisRS) as an example, we found an expressed 171-amino acid protein (HisRSΔCD) that deleted the entire CD, and joined an N-terminal WHEP to the C-terminal anticodon-binding domain (ABD). X-ray crystallography and three-dimensional NMR revealed the structures of human HisRS and HisRSΔCD. In contrast to homodimeric HisRS, HisRSΔCD is monomeric, where rupture of the ABD's packing with CD resulted in a dumbbell-like structure of flexibly linked WHEP and ABD domains. In addition, the ABD of HisRSΔCD presents a distinct local conformation. This natural internally deleted HisRS suggests evolutionary pressure to reshape AARS tertiary and quaternary structures for repurposing.
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.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Xu
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Wei
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zhou
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Wing-Sze
authors.initials: WS
authors.lastname: Lo
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Ching-Fun
authors.initials: CF
authors.lastname: Lau
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology; D001483:Base Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000235:genetics; D019143:Evolution, Molecular; D059014:High-Throughput Nucleotide Sequencing; D006643:Histidine-tRNA Ligase / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000097:blood / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009220:Myositis / Q000097:blood / Q000276:immunology; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D059467:Transcriptome
chemical_list: D000906:Antibodies; D018076:DNA, Complementary; D020033:Protein Isoforms; D006643:Histidine-tRNA Ligase