Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription

Yifat Ofir-Birin; Pengfei Fang; Steven P. Bennett; Hui Min Zhang; Jing Wang; Inbal Rachmin; Ryan Shapiro; Jing Song; Arie Dagan; Jorge Pozo; Sunghoon Kim; Alan G. Marshall; Paul Schimmel; Xiang Lei Yang; Hovav Nechushtan; Ehud Razin; Min Guo

doi:10.1016/j.molcel.2012.10.010

Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription

Yifat Ofir-Birin, Pengfei Fang, Steven P. Bennett, Hui Min Zhang, Jing Wang, Inbal Rachmin, Ryan Shapiro, Jing Song, Arie Dagan, Jorge Pozo, Sunghoon Kim, Alan G. Marshall, Paul Schimmel, Xiang Lei Yang, Hovav Nechushtan, Ehud Razin, Min Guo

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

58 Citations (Scopus)

Abstract

Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap₄A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.

Original language	English
Pages (from-to)	30-42
Number of pages	13
Journal	Molecular Cell
Volume	49
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2012.10.010
Publication status	Published - 2013 Jan 10

Bibliographical note

Funding Information:
We thank John Cleveland for critical review and editing of the manuscript. Use of the Advanced Photon Source and Advanced Light Source was supported by the U.S. Department of Energy under contract number DE-AC02-06CH11357, DE-AC02-05CH11231. This work was supported in part by grants from NIH (GM088278 [X.-L.Y.], GM23562 [P.S.], GM78359 [A.G.M.], GM100136 [M.G.]); by NSF Division of Materials Research through DMR-06-54118 (A.G.M.); by a fellowship from the National Foundation for Cancer Research; by the Global Frontier Project (NRF-M1AXA002-2012M3A6A4054273) and the WCU project (R31-2008-000-10103-0) of the Ministry of Education, Science, and Technology, Korea (S.K.); by the Israel Science Foundation, the United States Binational Science Foundation, the National Research Foundation of Singapore (HUJ-CREATE), the German-Israel Foundation for Scientific Research and Development, the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ), and Israel’s Ministry of Science and Technology (MOST) (E.R.); and by funding from the state of Florida to Scripps Florida (M.G.). E.R. and M.G. designed the experiments. Y.O.-B., P.F., S.P.B., H.-M.Z., J.W., I.R., R.S., J.S., A.D., and J.P. performed the experiments. Y.O.-B., P.F., S.P.B., H-M.Z., H.N., and M.G. analyzed the data. Y.O.-B., P.F., S.P.B., H.-M.Z., S.K., A.G.M., X.-L.Y., P.S., E.R., and M.G. wrote the paper. All authors discussed the results and commented on the manuscript.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2012.10.010

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Ofir-Birin, Y., Fang, P., Bennett, S. P., Zhang, H. M., Wang, J., Rachmin, I., Shapiro, R., Song, J., Dagan, A., Pozo, J., Kim, S., Marshall, A. G., Schimmel, P., Yang, X. L., Nechushtan, H., Razin, E., & Guo, M. (2013). Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription. Molecular Cell, 49(1), 30-42. https://doi.org/10.1016/j.molcel.2012.10.010

@article{9fa9d680622a474f8594f73f1caa86a9,

title = "Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription",

abstract = "Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.",

author = "Yifat Ofir-Birin and Pengfei Fang and Bennett, {Steven P.} and Zhang, {Hui Min} and Jing Wang and Inbal Rachmin and Ryan Shapiro and Jing Song and Arie Dagan and Jorge Pozo and Sunghoon Kim and Marshall, {Alan G.} and Paul Schimmel and Yang, {Xiang Lei} and Hovav Nechushtan and Ehud Razin and Min Guo",

note = "Funding Information: We thank John Cleveland for critical review and editing of the manuscript. Use of the Advanced Photon Source and Advanced Light Source was supported by the U.S. Department of Energy under contract number DE-AC02-06CH11357, DE-AC02-05CH11231. This work was supported in part by grants from NIH (GM088278 [X.-L.Y.], GM23562 [P.S.], GM78359 [A.G.M.], GM100136 [M.G.]); by NSF Division of Materials Research through DMR-06-54118 (A.G.M.); by a fellowship from the National Foundation for Cancer Research; by the Global Frontier Project (NRF-M1AXA002-2012M3A6A4054273) and the WCU project (R31-2008-000-10103-0) of the Ministry of Education, Science, and Technology, Korea (S.K.); by the Israel Science Foundation, the United States Binational Science Foundation, the National Research Foundation of Singapore (HUJ-CREATE), the German-Israel Foundation for Scientific Research and Development, the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ), and Israel{\textquoteright}s Ministry of Science and Technology (MOST) (E.R.); and by funding from the state of Florida to Scripps Florida (M.G.). E.R. and M.G. designed the experiments. Y.O.-B., P.F., S.P.B., H.-M.Z., J.W., I.R., R.S., J.S., A.D., and J.P. performed the experiments. Y.O.-B., P.F., S.P.B., H-M.Z., H.N., and M.G. analyzed the data. Y.O.-B., P.F., S.P.B., H.-M.Z., S.K., A.G.M., X.-L.Y., P.S., E.R., and M.G. wrote the paper. All authors discussed the results and commented on the manuscript. ",

year = "2013",

month = jan,

day = "10",

doi = "10.1016/j.molcel.2012.10.010",

language = "English",

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journal = "Molecular Cell",

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T1 - Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription

AU - Ofir-Birin, Yifat

AU - Fang, Pengfei

AU - Bennett, Steven P.

AU - Zhang, Hui Min

AU - Wang, Jing

AU - Rachmin, Inbal

AU - Shapiro, Ryan

AU - Song, Jing

AU - Dagan, Arie

AU - Pozo, Jorge

AU - Kim, Sunghoon

AU - Marshall, Alan G.

AU - Schimmel, Paul

AU - Yang, Xiang Lei

AU - Nechushtan, Hovav

AU - Razin, Ehud

AU - Guo, Min

N1 - Funding Information: We thank John Cleveland for critical review and editing of the manuscript. Use of the Advanced Photon Source and Advanced Light Source was supported by the U.S. Department of Energy under contract number DE-AC02-06CH11357, DE-AC02-05CH11231. This work was supported in part by grants from NIH (GM088278 [X.-L.Y.], GM23562 [P.S.], GM78359 [A.G.M.], GM100136 [M.G.]); by NSF Division of Materials Research through DMR-06-54118 (A.G.M.); by a fellowship from the National Foundation for Cancer Research; by the Global Frontier Project (NRF-M1AXA002-2012M3A6A4054273) and the WCU project (R31-2008-000-10103-0) of the Ministry of Education, Science, and Technology, Korea (S.K.); by the Israel Science Foundation, the United States Binational Science Foundation, the National Research Foundation of Singapore (HUJ-CREATE), the German-Israel Foundation for Scientific Research and Development, the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ), and Israel’s Ministry of Science and Technology (MOST) (E.R.); and by funding from the state of Florida to Scripps Florida (M.G.). E.R. and M.G. designed the experiments. Y.O.-B., P.F., S.P.B., H.-M.Z., J.W., I.R., R.S., J.S., A.D., and J.P. performed the experiments. Y.O.-B., P.F., S.P.B., H-M.Z., H.N., and M.G. analyzed the data. Y.O.-B., P.F., S.P.B., H.-M.Z., S.K., A.G.M., X.-L.Y., P.S., E.R., and M.G. wrote the paper. All authors discussed the results and commented on the manuscript.

PY - 2013/1/10

Y1 - 2013/1/10

N2 - Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.

AB - Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.

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JO - Molecular Cell

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Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

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