title: Structural context for mobilization of a human tRNA synthetase from its cytoplasmic complex.
abstract: Human lysyl-tRNA synthetase is bound to the multi-tRNA synthetase complex (MSC) that maintains and regulates the aminoacylation and nuclear functions of LysRS. The p38 scaffold protein binds LysRS to the MSC and, only with the appropriate cue, mobilizes LysRS for redirection to the nucleus to interact with the microphthalmia associated transcription factor (MITF). In recent work, an (α(2))(2) LysRS tetramer crystallized to yield a high-resolution structure and raised the question of how LysRS is arranged (dimer or tetramer) in the MSC to interact with p38. To understand the structural organization of the LysRS-p38 complex that regulates LysRS mobilization, we investigated the complex by use of small angle X-ray scattering and hydrogen-deuterium exchange with mass spectrometry in solution. The structure revealed a surprising α(2)β(1):β(1)α(2) organization in which a dimeric p38 scaffold holds two LysRS α(2) dimers in a parallel configuration. Each of the N-terminal 48 residues of p38 binds one LysRS dimer and, in so doing, brings two copies of the LysRS dimer into the MSC. The results suggest that this unique geometry, which reconfigures the LysRS tetramer from α(2):α(2) to α(2)β(1):β(1)α(2), is designed to control both retention and mobilization of LysRS from the MSC.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Fang
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Zhang
authors.forename: Ryan
authors.initials: R
authors.lastname: Shapiro
authors.forename: Alan G
authors.initials: AG
authors.lastname: Marshall
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Guo
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000201:enzymology*; D041961:Deuterium Exchange Measurement; D006801:Humans; D008250:Lysine-tRNA Ligase / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances / Q000737:chemistry*; D013058:Mass Spectrometry; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D053838:Scattering, Small Angle
chemical_list: D046911:Macromolecular Substances; D000604:Amino Acyl-tRNA Synthetases; D008250:Lysine-tRNA Ligase