The Ribosome as an Optimal Decoder: A Lesson in Molecular Recognition

The ribosome is a complex molecular machine that, in order to synthesize proteins, has to decode mRNAs by pairing their codons with matching tRNAs. Decoding is a major determinant of fitness and requires accurate and fast selection of correct tRNAs among many similar competitors. However, it is unclear whether the modern ribosome, and in particular its large conformational changes during decoding, are the outcome of adaptation to its task as a decoder or the result of other constraints. Here, we derive the energy landscape that provides optimal discrimination between competing substrates and thereby optimal tRNA decoding. We show that the measured landscape of the prokaryotic ribosome is sculpted in this way. This model suggests that conformational changes of the ribosome and tRNA during decoding are means to obtain an optimal decoder. Our analysis puts forward a generic mechanism that may be utilized broadly by molecular recognition systems.

[1]  Yong-Gui Gao,et al.  The Crystal Structure of the Ribosome Bound to EF-Tu and Aminoacyl-tRNA , 2009, Science.

[2]  J. Onuchic,et al.  Connecting energy landscapes with experimental rates for aminoacyl-tRNA accommodation in the ribosome. , 2010, Journal of the American Chemical Society.

[3]  J. Ninio.  Kinetic amplification of enzyme discrimination. , 1975, Biochimie.

[4]  M. Rodnina,et al.  Streptomycin interferes with conformational coupling between codon recognition and GTPase activation on the ribosome , 2004, Nature Structural &Molecular Biology.

[5]  Florence Tama,et al.  Excited states of ribosome translocation revealed through integrative molecular modeling , 2011, Proceedings of the National Academy of Sciences.

[6]  J. Puglisi,et al.  tRNA selection and kinetic proofreading in translation , 2004, Nature Structural &Molecular Biology.

[7]  Christian M T Spahn,et al.  Navigating the ribosome's metastable energy landscape. , 2009, Trends in biochemical sciences.

[8]  James B. Munro,et al.  Dynamic views of ribosome function: Energy landscapes and ensembles , 2011 .

[9]  J. Puglisi,et al.  The role of fluctuations in tRNA selection by the ribosome , 2007, Proceedings of the National Academy of Sciences.

[10]  Daniel Herschlag,et al.  The role of induced fit and conformational changes of enzymes in specificity and catalysis , 1988 .

[11]  Magnus Johansson,et al.  Rate and accuracy of bacterial protein synthesis revisited. , 2008, Current opinion in microbiology.

[12]  T. Pape,et al.  Induced fit in initial selection and proofreading of aminoacyl‐tRNA on the ribosome , 1999, The EMBO journal.

[13]  Alexander Schug,et al.  From protein folding to protein function and biomolecular binding by energy landscape theory. , 2010, Current opinion in pharmacology.

[14]  A. Bashan,et al.  Correlating ribosome function with high-resolution structures. , 2008, Trends in microbiology.

[15]  Tina Daviter,et al.  A uniform response to mismatches in codon-anticodon complexes ensures ribosomal fidelity. , 2006, Molecular cell.

[16]  M. Ehrenberg,et al.  Costs of accuracy determined by a maximal growth rate constraint , 1984, Quarterly Reviews of Biophysics.

[17]  C. Post,et al.  Reexamination of induced fit as a determinant of substrate specificity in enzymatic reactions. , 1995, Biochemistry.

[18]  Hani S. Zaher,et al.  Fidelity at the Molecular Level: Lessons from Protein Synthesis , 2009, Cell.

[19]  Susan Lindquist,et al.  Prions as adaptive conduits of memory and inheritance , 2005, Nature Reviews Genetics.

[20]  Rachel Green,et al.  Hyperaccurate and error-prone ribosomes exploit distinct mechanisms during tRNA selection. , 2010, Molecular cell.

[21]  E. Westhof,et al.  A new understanding of the decoding principle on the ribosome , 2012, Nature.

[22]  C. Dekker,et al.  Mechanism of homology recognition in DNA recombination from dual-molecule experiments. , 2012, Molecular cell.

[23]  J. Frank,et al.  A twisted tRNA intermediate sets the threshold for decoding. , 2003, RNA.

[24]  José N Onuchic,et al.  Accommodation of aminoacyl-tRNA into the ribosome involves reversible excursions along multiple pathways. , 2010, RNA.

[25]  Klaus Schulten,et al.  Ribosome-induced changes in elongation factor Tu conformation control GTP hydrolysis , 2009, Proceedings of the National Academy of Sciences.

[26]  M. Rodnina,et al.  Kinetic determinants of high-fidelity tRNA discrimination on the ribosome. , 2004, Molecular cell.

[27]  C. Kurland,et al.  Media dependence of translational mutant phenotype , 1988 .

[28]  P. Wolynes,et al.  On the role of frustration in the energy landscapes of allosteric proteins , 2011, Proceedings of the National Academy of Sciences.

[29]  Tsvi Tlusty,et al.  Optimal Design of a Molecular Recognizer: Molecular Recognition as a Bayesian Signal Detection Problem , 2008, IEEE Journal of Selected Topics in Signal Processing.

[30]  V. Ramakrishnan,et al.  First published online as a Review in Advance on February 25, 2005 STRUCTURAL INSIGHTS INTO TRANSLATIONAL , 2022 .

[31]  Colin Echeverría Aitken,et al.  Translation at the single-molecule level. , 2008, Annual review of biochemistry.

[32]  J. Hopfield.  Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Joachim Frank,et al.  The role of tRNA as a molecular spring in decoding, accommodation, and peptidyl transfer , 2005, FEBS letters.

[34]  M. Rodnina,et al.  Fidelity of aminoacyl-tRNA selection on the ribosome: kinetic and structural mechanisms. , 2001, Annual review of biochemistry.

[35]  V. Ramakrishnan,et al.  What recent ribosome structures have revealed about the mechanism of translation , 2009, Nature.

[36]  D. Turner,et al.  Thermodynamic parameters for an expanded nearest-neighbor model for formation of RNA duplexes with Watson-Crick base pairs. , 1998, Biochemistry.

[37]  M. Ehrenberg,et al.  Rate and accuracy of messenger RNA translation on the ribosome , 2011 .

[38]  V. Ramakrishnan,et al.  Recognition of Cognate Transfer RNA by the 30S Ribosomal Subunit , 2001, Science.

[39]  M. Ehrenberg,et al.  Genetic code translation displays a linear trade-off between efficiency and accuracy of tRNA selection , 2011, Proceedings of the National Academy of Sciences.

[40]  C. Kurland,et al.  Translational accuracy and the fitness of bacteria. , 1992, Annual review of genetics.

[41]  Tsvi Tlusty,et al.  Molecular recognition as an information channel: The role of conformational changes , 2009, 2009 43rd Annual Conference on Information Sciences and Systems.

[42]  Carl W. Helstrom,et al.  Elements of signal detection and estimation , 1994 .

[43]  V. Ramakrishnan,et al.  Selection of tRNA by the Ribosome Requires a Transition from an Open to a Closed Form , 2002, Cell.

[44]  Wei Zhang,et al.  GTPase activation of elongation factor EF‐Tu by the ribosome during decoding , 2009, The EMBO journal.

[45]  A. Fersht.  Enzyme structure and mechanism , 1977 .

[46]  J. Ninio.  Multiple stages in codon-anticodon recognition: double-trigger mechanisms and geometric constraints. , 2006, Biochimie.

[47]  T. Tlusty,et al.  RecA-mediated homology search as a nearly optimal signal detection system. , 2010, Molecular cell.

[48]  C. Kurland,et al.  Codon‐specific missense errors in vivo. , 1983, The EMBO journal.

[49]  D. Herries.  Enzyme structure and mechanism (second edition), by Alan Fersht. Pp 475. W H Freeman, New York. 1984. £28.95 or £14.95 (paperback) ISBN 0–7167–1614–3 or ISBN 0–7167–1615–1 (pbk) , 1985 .

[50]  A. R. Fresht.  Structure and Mechanism in Protein Science: A Guide to Enzyme Catalysis and Protein Folding , 1999 .