The Conformational Change in Elongation Factor Tu Involves Separation of Its Domains
Abstract
Elongation factor Tu (EF-Tu) is a highly conserved GTPase that is responsible for supplying the aminoacylated tRNA to the ribosome. Upon binding to the ribosome, EF-Tu undergoes GTP hydrolysis, which drives a major conformational change, triggering the release of aminoacylated tRNA to the ribosome. Using a combination of molecular simulation techniques, we studied the transition between the pre- and post-hydrolysis structures through two distinct pathways. Here, we show that the transition free energy is minimal along a non-intuitive pathway that involves “separation” of the GTP binding domain (domain 1) from the OB folds (domains 2 and 3), followed by domain 1 rotation, and, eventually, locking the EF-Tu conformation in the post-hydrolysis state. The domain separation also leads to a slight extension of the linker connecting domain 1 to domain 2. Using docking tools and correlation-based analysis, we identified and characterized the EF-Tu conformations that release the tRNA. These calculations suggest that EF-Tu can release the tRNA before the domains separate and after domain 1 rotates by 25°. Lastly, we also examined the EF-Tu conformations in the context of the ribosome. Given the high degrees of sequence similarity with other translational GTPases, we predict a similar separation mechanism is followed.
- Authors:
-
[1];
- Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry
- Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry; Univ. of Illinois, Urbana-Champaign, IL (United States). Center for the Physics of Living Cells; Univ. of Illinois, Urbana-Champaign, IL (United States). Beckman Inst.; Univ. of Illinois, Urbana-Champaign, IL (United States). Carl Woese Inst. for Genomic Biology
- Publication Date:
- Research Org.:
- Univ. of Illinois at Urbana-Champaign, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)
- OSTI Identifier:
- 1410674
- Grant/Contract Number:
- SC0005435; R01GM116961
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Biochemistry
- Additional Journal Information:
- Journal Volume: 56; Journal Issue: 45; Journal ID: ISSN 0006-2960
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Lai, Jonathan, Ghaemi, Zhaleh, and Luthey-Schulten, Zaida. The Conformational Change in Elongation Factor Tu Involves Separation of Its Domains. United States: N. p., 2017.
Web. doi:10.1021/acs.biochem.7b00591.
Lai, Jonathan, Ghaemi, Zhaleh, & Luthey-Schulten, Zaida. The Conformational Change in Elongation Factor Tu Involves Separation of Its Domains. United States. https://doi.org/10.1021/acs.biochem.7b00591
Lai, Jonathan, Ghaemi, Zhaleh, and Luthey-Schulten, Zaida. Wed .
"The Conformational Change in Elongation Factor Tu Involves Separation of Its Domains". United States. https://doi.org/10.1021/acs.biochem.7b00591. https://www.osti.gov/servlets/purl/1410674.
@article{osti_1410674,
title = {The Conformational Change in Elongation Factor Tu Involves Separation of Its Domains},
author = {Lai, Jonathan and Ghaemi, Zhaleh and Luthey-Schulten, Zaida},
abstractNote = {Elongation factor Tu (EF-Tu) is a highly conserved GTPase that is responsible for supplying the aminoacylated tRNA to the ribosome. Upon binding to the ribosome, EF-Tu undergoes GTP hydrolysis, which drives a major conformational change, triggering the release of aminoacylated tRNA to the ribosome. Using a combination of molecular simulation techniques, we studied the transition between the pre- and post-hydrolysis structures through two distinct pathways. Here, we show that the transition free energy is minimal along a non-intuitive pathway that involves “separation” of the GTP binding domain (domain 1) from the OB folds (domains 2 and 3), followed by domain 1 rotation, and, eventually, locking the EF-Tu conformation in the post-hydrolysis state. The domain separation also leads to a slight extension of the linker connecting domain 1 to domain 2. Using docking tools and correlation-based analysis, we identified and characterized the EF-Tu conformations that release the tRNA. These calculations suggest that EF-Tu can release the tRNA before the domains separate and after domain 1 rotates by 25°. Lastly, we also examined the EF-Tu conformations in the context of the ribosome. Given the high degrees of sequence similarity with other translational GTPases, we predict a similar separation mechanism is followed.},
doi = {10.1021/acs.biochem.7b00591},
journal = {Biochemistry},
number = 45,
volume = 56,
place = {United States},
year = {Wed Oct 18 00:00:00 EDT 2017},
month = {Wed Oct 18 00:00:00 EDT 2017}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 9 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Modeling the mechanisms of biological GTP hydrolysis
journal, September 2015
- Carvalho, Alexandra T. P.; Szeler, Klaudia; Vavitsas, Konstantinos
- Archives of Biochemistry and Biophysics, Vol. 582
Targeted molecular dynamics: A new approach for searching pathways of conformational transitions
journal, June 1994
- Schlitter, J.; Engels, M.; Krüger, P.
- Journal of Molecular Graphics, Vol. 12, Issue 2
Exploring Residue Component Contributions to Dynamical Network Models of Allostery
journal, July 2012
- VanWart, Adam T.; Eargle, John; Luthey-Schulten, Zaida
- Journal of Chemical Theory and Computation, Vol. 8, Issue 8
Structural insights into cognate versus near-cognate discrimination during decoding: Unique ribosome binding of near-cognate species
journal, March 2011
- Agirrezabala, Xabier; Schreiner, Eduard; Trabuco, Leonardo G.
- The EMBO Journal, Vol. 30, Issue 8
Impact of 2′-hydroxyl sampling on the conformational properties of RNA: Update of the CHARMM all-atom additive force field for RNA
journal, April 2011
- Denning, Elizabeth J.; Priyakumar, U. Deva; Nilsson, Lennart
- Journal of Computational Chemistry, Vol. 32, Issue 9
Tuning the affinity of aminoacyl-tRNA to elongation factor Tu for optimal decoding
journal, March 2011
- Schrader, J. M.; Chapman, S. J.; Uhlenbeck, O. C.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 13
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility
journal, December 2009
- Morris, Garrett M.; Huey, Ruth; Lindstrom, William
- Journal of Computational Chemistry, Vol. 30, Issue 16
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading
journal, January 2009
- Trott, Oleg; Olson, Arthur J.
- Journal of Computational Chemistry
Delayed Release of Inorganic Phosphate from Elongation Factor Tu Following GTP Hydrolysis on the Ribosome †
journal, October 2006
- Kothe, Ute; Rodnina, Marina V.
- Biochemistry, Vol. 45, Issue 42
Scalable molecular dynamics with NAMD
journal, January 2005
- Phillips, James C.; Braun, Rosemary; Wang, Wei
- Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
Elongation factor Tu, a GTPase triggered by codon recognition on the ribosome: mechanism and GTP consumption
journal, December 1995
- Rodnina, Marina V.; Pape, Tillmann; Fricke, Rainer
- Biochemistry and Cell Biology, Vol. 73, Issue 11-12
From A to B in free energy space
journal, February 2007
- Branduardi, Davide; Gervasio, Francesco Luigi; Parrinello, Michele
- The Journal of Chemical Physics, Vol. 126, Issue 5
Ensemble cryo-EM elucidates the mechanism of translation fidelity
journal, May 2017
- Loveland, Anna B.; Demo, Gabriel; Grigorieff, Nikolaus
- Nature, Vol. 546, Issue 7656
Ribosome dynamics during decoding
journal, March 2017
- Rodnina, Marina V.; Fischer, Niels; Maracci, Cristina
- Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 372, Issue 1716
Kinetic Mechanism of Elongation Factor Ts-Catalyzed Nucleotide Exchange in Elongation Factor Tu †
journal, January 2002
- Gromadski, Kirill B.; Wieden, Hans-Joachim; Rodnina, Marina V.
- Biochemistry, Vol. 41, Issue 1
Converting structural information into an allosteric-energy-based picture for elongation factor Tu activation by the ribosome
journal, May 2011
- Adamczyk, A. J.; Warshel, A.
- Proceedings of the National Academy of Sciences, Vol. 108, Issue 24
GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit
journal, February 2013
- Pronk, Sander; Páll, Szilárd; Schulz, Roland
- Bioinformatics, Vol. 29, Issue 7
A Catalytic Mechanism for Cysteine N-Terminal Nucleophile Hydrolases, as Revealed by Free Energy Simulations
journal, February 2012
- Lodola, Alessio; Branduardi, Davide; De Vivo, Marco
- PLoS ONE, Vol. 7, Issue 2
SMOG@ctbp: simplified deployment of structure-based models in GROMACS
journal, June 2010
- Noel, Jeffrey K.; Whitford, Paul C.; Sanbonmatsu, Karissa Y.
- Nucleic Acids Research, Vol. 38, Issue suppl_2
EF-Tu dynamics during pre-translocation complex formation: EF-Tu·GDP exits the ribosome via two different pathways
journal, September 2015
- Liu, Wei; Chen, Chunlai; Kavaliauskas, Darius
- Nucleic Acids Research, Vol. 43, Issue 19
How EF-Tu can contribute to efficient proofreading of aa-tRNA by the ribosome
journal, October 2016
- Noel, Jeffrey K.; Whitford, Paul C.
- Nature Communications, Vol. 7, Issue 1
A unified formulation of the constant temperature molecular dynamics methods
journal, July 1984
- Nosé, Shuichi
- The Journal of Chemical Physics, Vol. 81, Issue 1
Generalized correlation for biomolecular dynamics
journal, December 2005
- Lange, Oliver F.; Grubmüller, Helmut
- Proteins: Structure, Function, and Bioinformatics, Vol. 62, Issue 4
PLUMED: A portable plugin for free-energy calculations with molecular dynamics
journal, October 2009
- Bonomi, Massimiliano; Branduardi, Davide; Bussi, Giovanni
- Computer Physics Communications, Vol. 180, Issue 10
Simulating Dynamics in RNA–Protein Complexes
book, January 2012
- Eargle, John; Luthey-Schulten, Zaida
- Nucleic Acids and Molecular Biology
Structure-function relationships of elongation factor Tu. Isolation and activity of the guanine-nucleotide-binding domain
journal, June 1989
- Jensen, Michael; Cool, Robbert H.; Mortensen, Kim K.
- European Journal of Biochemistry, Vol. 182, Issue 2
WebLogo: A Sequence Logo Generator
journal, May 2004
- Crooks, Gavin E.; Hon, Gary; Chandonia, John-Marc
- Genome Research, Vol. 14, Issue 6, p. 1188-1190
Ribosome-induced tuning of GTP hydrolysis by a translational GTPase
journal, September 2014
- Maracci, Cristina; Peske, Frank; Dannies, Ev
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 40
The role of tRNA as a molecular spring in decoding, accommodation, and peptidyl transfer
journal, November 2004
- Frank, Joachim; Sengupta, Jayati; Gao, Haixiao
- FEBS Letters, Vol. 579, Issue 4
Mechanism of activation of elongation factor Tu by ribosome: Catalytic histidine activates GTP by protonation
journal, July 2013
- Aleksandrov, A.; Field, M.
- RNA, Vol. 19, Issue 9
Dynamics of Recognition between tRNA and Elongation Factor Tu
journal, April 2008
- Eargle, John; Black, Alexis A.; Sethi, Anurag
- Journal of Molecular Biology, Vol. 377, Issue 5, p. 1382-1405
The evolutionary and functional diversity of classical and lesser-known cytoplasmic and organellar translational GTPases across the tree of life
journal, February 2015
- Atkinson, Gemma Catherine
- BMC Genomics, Vol. 16, Issue 1
Induced fit in initial selection and proofreading of aminoacyl-tRNA on the ribosome
journal, July 1999
- Pape, T.
- The EMBO Journal, Vol. 18, Issue 13
The crystal structure of Cys-tRNACys–EF-Tu–GDPNP reveals general and specific features in the ternary complex and in tRNA
journal, February 1999
- Nissen, Poul; Thirup, Søren; Kjeldgaard, Morten
- Structure, Vol. 7, Issue 2
Review: Translational GTPases
journal, May 2016
- Maracci, Cristina; Rodnina, Marina V.
- Biopolymers, Vol. 105, Issue 8
How Robust Are Protein Folding Simulations with Respect to Force Field Parameterization?
journal, May 2011
- Piana, Stefano; Lindorff-Larsen, Kresten; Shaw, David E.
- Biophysical Journal, Vol. 100, Issue 9
LINCS: A linear constraint solver for molecular simulations
journal, September 1997
- Hess, Berk; Bekker, Henk; Berendsen, Herman J. C.
- Journal of Computational Chemistry, Vol. 18, Issue 12
Well-Tempered Metadynamics: A Smoothly Converging and Tunable Free-Energy Method
journal, January 2008
- Barducci, Alessandro; Bussi, Giovanni; Parrinello, Michele
- Physical Review Letters, Vol. 100, Issue 2
Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ 1 and χ 2 Dihedral Angles
journal, August 2012
- Best, Robert B.; Zhu, Xiao; Shim, Jihyun
- Journal of Chemical Theory and Computation, Vol. 8, Issue 9
Structure-Function Relationships of the G Domain, a Canonical Switch Motif
journal, July 2011
- Wittinghofer, Alfred; Vetter, Ingrid R.
- Annual Review of Biochemistry, Vol. 80, Issue 1
Structural Snapshots of Actively Translating Human Ribosomes
journal, May 2015
- Behrmann, Elmar; Loerke, Justus; Budkevich, Tatyana V.
- Cell, Vol. 161, Issue 4
A Kinetic Safety Gate Controlling the Delivery of Unnatural Amino Acids to the Ribosome
journal, October 2013
- Mittelstaet, Joerg; Konevega, Andrey L.; Rodnina, Marina V.
- Journal of the American Chemical Society, Vol. 135, Issue 45
Canonical dynamics: Equilibrium phase-space distributions
journal, March 1985
- Hoover, William G.
- Physical Review A, Vol. 31, Issue 3
Modulation of Chemical Composition and Other Parameters of the Cell at Different Exponential Growth Rates
journal, September 2008
- Dennis, Patrick P.; Bremer, Hans
- EcoSal Plus, Vol. 3, Issue 1
Experimental and computational determination of tRNA dynamics
journal, November 2009
- Alexander, Rebecca W.; Eargle, John; Luthey-Schulten, Zaida
- FEBS Letters, Vol. 584, Issue 2
A simple method to control over-alignment in the MAFFT multiple sequence alignment program
journal, February 2016
- Katoh, Kazutaka; Standley, Daron M.
- Bioinformatics, Vol. 32, Issue 13
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models
journal, October 1992
- Miyamoto, Shuichi; Kollman, Peter A.
- Journal of Computational Chemistry, Vol. 13, Issue 8
Dynamical networks in tRNA:protein complexes
journal, April 2009
- Sethi, A.; Eargle, J.; Black, A. A.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 16
Exceptionally large entropy contributions enable the high rates of GTP hydrolysis on the ribosome
journal, October 2015
- Åqvist, Johan; Kamerlin, Shina C. L.
- Scientific Reports, Vol. 5, Issue 1
Die Berechnung optischer und elektrostatischer Gitterpotentiale
journal, January 1921
- Ewald, P. P.
- Annalen der Physik, Vol. 369, Issue 3
Helix unwinding in the effector region of elongation factor EF-Tu–GDP
journal, October 1996
- Polekhina, Galina; Thirup, Søren; Kjeldgaard, Morten
- Structure, Vol. 4, Issue 10
Complete kinetic mechanism of elongation factor Tu-dependent binding of aminoacyl-tRNA to the A site of the E.coli ribosome
journal, December 1998
- Pape, T.
- The EMBO Journal, Vol. 17, Issue 24
The Crystal Structure of the Ribosome Bound to EF-Tu and Aminoacyl-tRNA
journal, October 2009
- Schmeing, T. M.; Voorhees, R. M.; Kelley, A. C.
- Science, Vol. 326, Issue 5953
VMD: Visual molecular dynamics
journal, February 1996
- Humphrey, William; Dalke, Andrew; Schulten, Klaus
- Journal of Molecular Graphics, Vol. 14, Issue 1
Exploring the Specificity of Bacterial Elongation Factor Tu for Different tRNAs
journal, May 2007
- Sanderson, Lee E.; Uhlenbeck, Olke C.
- Biochemistry, Vol. 46, Issue 21
The elongation factor Tu binds aminoacyl-tRNA in the presence of GDP.
journal, October 1982
- Pingoud, A.; Block, W.; Wittinghofer, A.
- Journal of Biological Chemistry, Vol. 257, Issue 19
Works referencing / citing this record:
Domain structure of HelD, an interaction partner of Bacillus subtilis RNA polymerase
journal, April 2019
- Kovaľ, Tomáš; Sudzinová, Petra; Perháčová, Terézia
- FEBS Letters, Vol. 593, Issue 9
Structural dynamics of translation elongation factor Tu during aa-tRNA delivery to the ribosome
journal, August 2018
- Kavaliauskas, Darius; Chen, Chunlai; Liu, Wei
- Nucleic Acids Research, Vol. 46, Issue 16
Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection
journal, February 2020
- Morse, Justin C.; Girodat, Dylan; Burnett, Benjamin J.
- Proceedings of the National Academy of Sciences, Vol. 117, Issue 7
Domain structure of HelD, an interaction partner of Bacillus subtilis RNA polymerase
text, January 2019
- Kovaľ, Tomáš; Sudzinová, Petra; Perháčová, Terézia
- Deutsches Elektronen-Synchrotron, DESY, Hamburg
Disorder guides domain rearrangement in elongation factor Tu
journal, October 2018
- Yang, Huan; Perrier, Jonathan; Whitford, Paul C.
- Proteins: Structure, Function, and Bioinformatics, Vol. 86, Issue 10
Elongation factor-Tu can repetitively engage aminoacyl-tRNA within the ribosome during the proofreading stage of tRNA selection
journal, February 2020
- Morse, Justin C.; Girodat, Dylan; Burnett, Benjamin J.
- Proceedings of the National Academy of Sciences, Vol. 117, Issue 7