Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Deng, Xiangyu; Qin, Xiangjing; Chen, Lei; Jia, Qian; Zhang, Yonghui; Zhang, Zhiyong; Lei, Dongsheng; Ren, Gang; Zhou, Zhihong; Wang, Zhong; Li, Qing; Xie, Wei

doi:10.1074/jbc.M115.679126

Title: Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Journal Article · Thu Jan 21 00:00:00 EST 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M115.679126· OSTI ID:1379154

Deng, Xiangyu ^[1]; Qin, Xiangjing ^[2]; Chen, Lei ^[1]; Jia, Qian ^[1]; Zhang, Yonghui ^[3]; Zhang, Zhiyong ^[3]; Lei, Dongsheng ^[4]; Ren, Gang ^[4]; Zhou, Zhihong ^[1]; Wang, Zhong ^[1]; Li, Qing ^[1]; Xie, Wei ^[1]

Sun Yat-Sen Univ., Guangzhou, (China)
Chinese Academy of Sciences (CAS), Guangzhou (China)
Univ. of Science and Technology of China, Hefei (China)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Glycyl-tRNA synthetase (GlyRS) is the enzyme that covalently links glycine to cognate tRNA for translation. It is of great interest because of its nonconserved quaternary structures, unique species-specific aminoacylation properties, and noncanonical functions in neurological diseases, but none of these is fully understood. We report two crystal structures of human GlyRS variants, in the free form and in complex with tRNA Gly respectively, and reveal new aspects of the glycylation mechanism. We discover that insertion 3 differs considerably in conformation in catalysis and that it acts like a "switch" and fully opens to allow tRNA to bind in a cross-subunit fashion. The flexibility of the protein is supported by molecular dynamics simulation, as well as enzymatic activity assays. The biophysical and biochemical studies suggest that human GlyRS may utilize its flexibility for both the traditional function (regulate tRNA binding) and alternative functions (roles in diseases).

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1379154

Journal Information:: Journal of Biological Chemistry, Vol. 291, Issue 11; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 11 works

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References (57)

Two Enzymically Active Forms of Glycyl-tRNA Synthetase from Bacillus brevis. Purification and Properties Surguchov, Andrei P.; Surguchova, Irina G. European Journal of Biochemistry, Vol. 54, Issue 1 https://doi.org/10.1111/j.1432-1033.1975.tb04127.x	journal	May 1975
Eleven down and nine to go Cusack, Stephen Nature Structural Biology, Vol. 2, Issue 10 https://doi.org/10.1038/nsb1095-824	journal	October 1995
Crystal Structures and Biochemical Analyses Suggest a Unique Mechanism and Role for Human Glycyl-tRNA Synthetase in Ap4A Homeostasis Guo, Rey-Ting; Chong, Yeeting E.; Guo, Min Journal of Biological Chemistry, Vol. 284, Issue 42 https://doi.org/10.1074/jbc.M109.030692	journal	August 2009
Charcot-Marie-Tooth Disease: A Clinico-genetic Confrontation: Charcot-Marie-Tooth Disease Barisic, N.; Claeys, K. G.; Sirotković-Skerlev, M. Annals of Human Genetics, Vol. 72, Issue 3 https://doi.org/10.1111/j.1469-1809.2007.00412.x	journal	January 2008
Aminoacyl tRNA Synthetases: General Scheme of Structure-Function Relationships in the Polypeptides and Recognition of Transfer RNAs Schimmel, Paul Annual Review of Biochemistry, Vol. 56, Issue 1 https://doi.org/10.1146/annurev.bi.56.070187.001013	journal	June 1987
The aminoacyl-tRNA synthetase family: Modules at work Delarue, M.; Moras, D. BioEssays, Vol. 15, Issue 10 https://doi.org/10.1002/bies.950151007	journal	October 1993
An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy Achilli, F.; Bros-Facer, V.; Williams, H. P. Disease Models & Mechanisms, Vol. 2, Issue 7-8 https://doi.org/10.1242/dmm.002527	journal	May 2009
Two novel mutations of GARS in Korean families with distal hereditary motor neuropathy type V Lee, Hye Jin; Park, Jin; Nakhro, Khriezanou Journal of the Peripheral Nervous System, Vol. 17, Issue 4 https://doi.org/10.1111/j.1529-8027.2012.00442.x	journal	December 2012
GROMACS 4: Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation Hess, Berk; Kutzner, Carsten; van der Spoel, David Journal of Chemical Theory and Computation, Vol. 4, Issue 3 https://doi.org/10.1021/ct700301q	journal	February 2008
Sequence, structure and evolutionary relationships between class 2 aminoacyl-tRNA synthetases: An update Cusack, S. Biochimie, Vol. 75, Issue 12 https://doi.org/10.1016/0300-9084(93)90006-E	journal	January 1993
Glycyl-tRNA synthetase from baker's yeast. Interconversion between active and inactive forms of the enzyme Kern, Daniel; Giege, Richard; Ebel, Jean Pierre Biochemistry, Vol. 20, Issue 1 https://doi.org/10.1021/bi00504a021	journal	January 1981
Searching for silver bullets: An alternative strategy for crystallizing macromolecules McPherson, Alexander; Cudney, Bob Journal of Structural Biology, Vol. 156, Issue 3 https://doi.org/10.1016/j.jsb.2006.09.006	journal	December 2006
DOG 1.0: illustrator of protein domain structures Ren, Jian; Wen, Longping; Gao, Xinjiao Cell Research, Vol. 19, Issue 2 https://doi.org/10.1038/cr.2009.6	journal	January 2009
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
An Example of Non-Conservation of Oligomeric Structure in Prokaryotic Aminoacyl-tRNA Synthetases. Biochemical and Structural Properties of Glycyl-tRNA Synthetase from Thermus thermophilus Mazauric, Marie-Helene; Reinbolt, Joseph; Lorber, Bernard European Journal of Biochemistry, Vol. 241, Issue 3 https://doi.org/10.1111/j.1432-1033.1996.00814.x	journal	November 1996
P-LINCS: A Parallel Linear Constraint Solver for Molecular Simulation Hess, Berk Journal of Chemical Theory and Computation, Vol. 4, Issue 1 https://doi.org/10.1021/ct700200b	journal	December 2007
tRNA synthetase counteracts c-Myc to develop functional vasculature Shi, Yi; Xu, Xiaoling; Zhang, Qian eLife, Vol. 3 https://doi.org/10.7554/eLife.02349	journal	June 2014
Comparison of simple potential functions for simulating liquid water Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D. The Journal of Chemical Physics, Vol. 79, Issue 2 https://doi.org/10.1063/1.445869	journal	July 1983
Genetic and clinical aspects of Charcot-Marie-Tooth's disease Skre, H. Clinical Genetics, Vol. 6, Issue 2 https://doi.org/10.1111/j.1399-0004.1974.tb00638.x	journal	August 1974
Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V Antonellis, Anthony; Ellsworth, Rachel E.; Sambuughin, Nyamkhishig The American Journal of Human Genetics, Vol. 72, Issue 5 https://doi.org/10.1086/375039	journal	May 2003
MSC p43 required for axonal development in motor neurons Zhu, Xiaodong; Liu, Yang; Yin, Yanqing Proceedings of the National Academy of Sciences, Vol. 106, Issue 37 https://doi.org/10.1073/pnas.0901872106	journal	August 2009
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins ^† MacKerell, A. D.; Bashford, D.; Bellott, M. The Journal of Physical Chemistry B, Vol. 102, Issue 18 https://doi.org/10.1021/jp973084f	journal	April 1998
Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy Jordanova, Albena; Irobi, Joy; Thomas, Florian P. Nature Genetics, Vol. 38, Issue 2 https://doi.org/10.1038/ng1727	journal	January 2006
Long-range structural effects of a Charcot Marie Tooth disease-causing mutation in human glycyl-tRNA synthetase Xie, W.; Nangle, L. A.; Zhang, W. Proceedings of the National Academy of Sciences, Vol. 104, Issue 24 https://doi.org/10.1073/pnas.0703908104	journal	June 2007
Inherited Peripheral Neuropathies Saporta, Mario A.; Shy, Michael E. Neurologic Clinics, Vol. 31, Issue 2 https://doi.org/10.1016/j.ncl.2013.01.009	journal	May 2013
GARS axonopathy: not every neuron's cup of tRNA Motley, William W.; Talbot, Kevin; Fischbeck, Kenneth H. Trends in Neurosciences, Vol. 33, Issue 2 https://doi.org/10.1016/j.tins.2009.11.001	journal	February 2010
Coexistence of CMT-2D and distal SMA-V phenotypes in an Italian family with a GARS gene mutation Del Bo, R.; Locatelli, F.; Corti, S. Neurology, Vol. 66, Issue 5 https://doi.org/10.1212/01.wnl.0000201275.18875.ac	journal	March 2006
Canonical sampling through velocity rescaling Bussi, Giovanni; Donadio, Davide; Parrinello, Michele The Journal of Chemical Physics, Vol. 126, Issue 1 https://doi.org/10.1063/1.2408420	journal	January 2007
A Major Determinant for Binding and Aminoacylation of tRNAAla in Cytoplasmic Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth Disease Latour, Philippe; Thauvin-Robinet, Christel; Baudelet-Méry, Chantal The American Journal of Human Genetics, Vol. 86, Issue 1 https://doi.org/10.1016/j.ajhg.2009.12.005	journal	January 2010
RNA-Dependent Cysteine Biosynthesis in Archaea Sauerwald, Anselm; Zhu, Wenhong; Major, Tiffany A. Science, Vol. 307, Issue 5717, p. 1969-1972 https://doi.org/10.1126/science.1108329	journal	March 2005
Severe childhood SMA and axonal CMT due to anticodon binding domain mutations in the GARS gene James, P. A.; Cader, M. Z.; Muntoni, F. Neurology, Vol. 67, Issue 9 https://doi.org/10.1212/01.wnl.0000242619.52335.bc	journal	November 2006
Motor nerve conduction velocity in peroneal muscular atrophy: evidence for genetic heterogeneity Thomas, P. K.; Calne, D. B. Journal of Neurology, Neurosurgery & Psychiatry, Vol. 37, Issue 1 https://doi.org/10.1136/jnnp.37.1.68	journal	January 1974
An Active Dominant Mutation of Glycyl-tRNA Synthetase Causes Neuropathy in a Charcot-Marie-Tooth 2D Mouse Model Seburn, Kevin L.; Nangle, Leslie A.; Cox, Gregory A. Neuron, Vol. 51, Issue 6 https://doi.org/10.1016/j.neuron.2006.08.027	journal	September 2006
The various Charcot–Marie–Tooth diseases Vallat, Jean-Michel; Mathis, Stéphane; Funalot, Benoît Current Opinion in Neurology, Vol. 26, Issue 5 https://doi.org/10.1097/WCO.0b013e328364c04b	journal	January 2013
Phenotype of Charcot-Marie-Tooth disease Type 2 Bienfait, H. M. E.; Baas, F.; Koelman, J. H. T. M. Neurology, Vol. 68, Issue 20 https://doi.org/10.1212/01.wnl.0000263479.97552.94	journal	May 2007
Quiet high-resolution computer models of a plasma Hockney, R. W.; Goel, S. P.; Eastwood, J. W. Journal of Computational Physics, Vol. 14, Issue 2 https://doi.org/10.1016/0021-9991(74)90010-2	journal	February 1974
Progesterone Stimulates the Activity of the Promoters of Peripheral Myelin Protein-22 and Protein Zero Genes in Schwann Cells Désarnaud, Frank; Do Thi, Anh N.; Brown, Adrienne M. Journal of Neurochemistry, Vol. 71, Issue 4 https://doi.org/10.1046/j.1471-4159.1998.71041765.x	journal	October 1998
Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations Sivakumar, Kumaraswamy; Kyriakides, Theodoros; Puls, Imke Brain, Vol. 128, Issue 10 https://doi.org/10.1093/brain/awh590	journal	July 2005
Molecular dynamics with coupling to an external bath Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F. The Journal of Chemical Physics, Vol. 81, Issue 8 https://doi.org/10.1063/1.448118	journal	October 1984
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Pyrrolysine Encoded by UAG in Archaea: Charging of a UAG-Decoding Specialized tRNA Srinivasan, G. Science, Vol. 296, Issue 5572 https://doi.org/10.1126/science.1069588	journal	May 2002
An operational RNA code for amino acids and variations in critical nucleotide sequences in evolution Schimmel, Paul Journal of Molecular Evolution, Vol. 40, Issue 5 https://doi.org/10.1007/BF00166621	journal	May 1995
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression Yannay-Cohen, Nurit; Carmi-Levy, Irit; Kay, Gillian Molecular Cell, Vol. 34, Issue 5 https://doi.org/10.1016/j.molcel.2009.05.019	journal	June 2009
Aminoacyl‐tRNA synthetases in medicine and disease Yao, Peng; Fox, Paul L. EMBO Molecular Medicine, Vol. 5, Issue 3 https://doi.org/10.1002/emmm.201100626	journal	February 2013
NMRPipe: A multidimensional spectral processing system based on UNIX pipes Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW. Journal of Biomolecular NMR, Vol. 6, Issue 3 https://doi.org/10.1007/BF00197809	journal	November 1995
Compound Heterozygosity for Loss-of-Function Lysyl-tRNA Synthetase Mutations in a Patient with Peripheral Neuropathy McLaughlin, Heather M.; Sakaguchi, Reiko; Liu, Cuiping The American Journal of Human Genetics, Vol. 87, Issue 4 https://doi.org/10.1016/j.ajhg.2010.09.008	journal	October 2010
Crystal structure of glycyl-tRNA synthetase from Thermus thermophilus. Logan, D. T.; Mazauric, M. H.; Kern, D. The EMBO Journal, Vol. 14, Issue 17 https://doi.org/10.1002/j.1460-2075.1995.tb00089.x	journal	September 1995
Charcot-Marie-Tooth Neuropathies: Diagnosis and Management Jani-Acsadi, Agnes; Krajewski, Karen; Shy, Michael Seminars in Neurology, Vol. 28, Issue 2 https://doi.org/10.1055/s-2008-1062264	journal	April 2008
Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs Eriani, Gilbert; Delarue, Marc; Poch, Olivier Nature, Vol. 347, Issue 6289, p. 203-206 https://doi.org/10.1038/347203a0	journal	September 1990
A smooth particle mesh Ewald method Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L. The Journal of Chemical Physics, Vol. 103, Issue 19 https://doi.org/10.1063/1.470117	journal	November 1995
On the Evolution of Structure in Aminoacyl-tRNA Synthetases O'Donoghue, P.; Luthey-Schulten, Z. Microbiology and Molecular Biology Reviews, Vol. 67, Issue 4 https://doi.org/10.1128/MMBR.67.4.550-573.2003	journal	December 2003
Two Distinct Cytokines Released from a Human Aminoacyl-tRNA Synthetase Wakasugi, K. Science, Vol. 284, Issue 5411 https://doi.org/10.1126/science.284.5411.147	journal	April 1999
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Glycyl- and alanyl-tRNA synthetases from Bombyx mori. Purification and properties. Dignam, S. S.; Dignam, J. D. Journal of Biological Chemistry, Vol. 259, Issue 7 https://doi.org/10.1016/S0021-9258(17)43007-9	journal	April 1984
Human glycyl-tRNA synthetase. Wide divergence of primary structure from bacterial counterpart and species-specific aminoacylation. Shiba, K.; Schimmel, P.; Motegi, H. Journal of Biological Chemistry, Vol. 269, Issue 47 https://doi.org/10.1016/S0021-9258(18)43986-5	journal	November 1994
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997

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