Rajan Sankaranarayanan

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1 Proofreading during translation of the genetic code Rajan Sankaranarayanan Centre for Cellular and Molecular Biology (CCMB) Council for Scientific and Industrial Research (CSIR) Hyderabad, INDIA

2 Accuracy during translation of the genetic code The fidelity of information transfer is carefully controlled at each step The levels of accuracy observed are the result of a balance between: 1) the need to preserve genetic information 2) to be flexible enough to allow adaptation to a changing environment. Nature, 443:7 (2006) 41-42

3 G N A S I D Q F Y L E H W M P T V C IRS VRS K R TRS

4 The problem of amino acid discrimination First proposed by Linus Pauling (1957). Difference of a single methyl group corresponds to a binding energy of 1 Kcal/mol and to an error rate of 1 in 5. Observed error rates are 1 in 3,500 to 40,000. How synthetases achieve such a high specificity? Isoleucine Valine Threonine Valine Threonine Serine Valine

5 Transfer-RNA mediated editing mechanism

6 Editing-defective trna synthetase causes protein misfolding and neurodegeneration Wild type (rear) sti/sti (front) Sticky (sti) mutant mice: Cerebellar Purkinje cell loss and ataxia Accumulation of misfolded proteins.. The sti mutation was identified in the editing domain of alanyl-trna synthetase the importance of the editing activity and hence the need to study the mechanism of editing in greater detail... Lee J. W. et. al. Nature., 2006

7 ThrRS trna complex from E. coli Editing Catalytic domain Aminoacylation/ charging Anticodon binding domain Translational repressor

8 Proofreading module of ThrRS is not conserved through evolution Eukaryotes Eubacteria Archaea Mycobacterium Anticodon Catalytic domain

9 Striking structural homology to D-tyr-tRNA deacylase DTD removes D-amino acids from misacylated trnas DTD Pab-NTD Rms deviation 1.2 Å for 112 C α DTDs identified in Eubacteria and Eukaryotes, but shown to be missing in archaea Not specific for trna but to any D-amino acid attached to trnas, like D-tyr-tRNA Tyr, D-trp-tRNA Trp, D-asp-tRNA Asp and Gly-tRNA Gly Ferri-Fioni et al. J. Biol. Chem. 2001; Soutourina et al. J. Biol. Chem 2004;

10 Perpetuation of Homochirality Protein with all D-amino acids is functional albeit with reversal of chirality in substrate selection. e.g. HIV-1 protease (Science, 1992) Intermittent substitution L- and D- enantiomers would result in a nonfunctional protein. How this Homochirality was effectively perpetuated so that it became an integral part of present day translational apparatus? Primordial synthetases must have played a crucial role in enforcing homochirality

11 A model for perpetuation of homochirality A weakly discriminating synthetase D-amino acid removing enzyme Minihelix or trna Dwivedi, S., Kruparani, S. P. and Sankaranarayanan, R. Nature Struct. Mol. Biol. (2005)

12 Post-transfer editing mechanism trna extremity switches from a helical to bent conformation Seryl-3 - adenosine analog Ser3AA

13 Pab-NTD complexes with post-transfer analog (L-Ser3AA) Electron density of L-ser3AA L-Ser3AA Surface representation Overall view of the complex Resolution: 1.86 Å R/R free :19.3/22.0 & Resolution: 2.25 Å R/R free :20.6/28.7 Structural basis of editing of L-ser-tRNA Thr Deacylation of ser-trna Thr by Pab-NTD and its mutants No side chain is directly involved The 2 OH of the trna may activate W1 to have a nucleophilic attack on the carbonyl carbon. archaeal ThrRS is proposed to use substrate-assisted catalysis for removing mischarged serine Hussain T. et. al. EMBO J., (2006) 25,

14 Proposed substrate-assisted editing mechanism in Pab-NTD Adenine76 Charged trna Free trna 2 OH of ribose Deacylation Ester bond Catalytic water Amino group of L-ser charged on trna Free L-serine Side chain OH of L-ser charged on trna 2 OH of trna is proposed to play a crucial role in editing of L-ser-tRNA Thr Hussain T. et. al. EMBO J., (2006) 25,

15 Editing-defective trna synthetase causes protein misfolding and neurodegeneration Wild type (rear) Mutant (front) Signs of neurodegeneration in mutant mice The mutation was identified in the editing domain of AlaRS Deacylation of Ser-tRNA Ala by WT and Mutant mouse AlaRS is nearly indistinguishable. Inset, aminoacylation control with the same enzyme dilution used in the experiment. Although the editing defect was only partial, a strong phenotype was seen in the mouse. Accumulation of misfolded proteins.. Lee J. W. et. al. Nature, 2006

16 Similar Editing-defective mutation in Pab-NTD Deacylation of Ser-tRNA Ala by WT and mutant Mouse AlaRS Deacylation of Ser-tRNA Thr by Pab-NTD and its mutants Position of Lys121 with respect to the substrate analog at the editing site in Pab-NTD

17 Pab-NTD wild type and K121M mutant complexes Ligands Wi ld type complexes K121M Mutant complexes L-Ser3AA (noncognate) 13 independent observations in 7 4 independent observations in 2 different crystals at resolutions: different crystals at resolutions: 1.86Å, 1.86Å, 1.96Å, 2.00Å, 1.79Å and 2.00Å. 2.20Å, 2.20Å and 2.25Å. L-Thr3AA (cognate) 4 independent observations in 2 different crystals at resolutions: 1.86Å and 2.20Å. 8 independent observations in 4 different crystals at resolutions: 1.86Å, 1.86Å, 2.00Å and 2.40Å. Gly3AA (smaller) 4 independent observations in 2 different crystals at resolutions: 2.00Å and 2.40Å. 4 independent observations in 2 different crystals at resolutions: 2.00Å and 2.40Å. D-Ser3AA (opposite chirality) 4 independent observations in 2 different crystals at resolutions: 2.10Å, and 2.80Å. 10 independent observations in 5 different crystals at resolutions: 1.86Å, 1.90Å, 1.91Å, 2.25Å and 2.51Å.

18 The Double-Sieve mechanism for the isoleucyl-trna synthetase Double-Sieve Model Catalytic Site: Coarse Sieve Hydrolytic Site: Fine Sieve Fersht, A. R. (1977) Enzyme Structure and Mechanism, W. H. Freeman, San Francisco, CA. The "strong" force in specificity is steric repulsion: Whereas a smaller substrate can always rattle around in a larger cavity, it is energetically very difficult to cram a larger substrate into a cavity built for a smaller one. On the basis of this idea, I proposed the "double-sieve" editing mechanism for sorting amino acids Fersht, AR (1998) Science Steric exclusion of cognate amino acid from the editing pocket was thought to be a universal mode of discrimination of cognate substrate. Threonyl-tRNA synthetase contains an additional functional site that hydrolyzes Ser-tRNA Thr but not Thr-tRNA Thr. The discrimination of serine from threonine is relatively easy because threonine contains an extra methyl group; a site that conforms to the structure of serine will sterically exclude threonine. Amino acid attached to trna and not free amino acid is the substrate.

19 Binding of cognate (Thr3AA) and noncognate (Ser3AA) substrate analogs in the editing domain (Pab-NTD) Editing domain Catalytic domain 15N 15N Anticodon binding domain Ser3AA trna Thr3AA 1HN Thr3AA Ser3AA Ligand 1HN Ser3AA ΔH Kcal/mole ± TΔS Kcal/mole ΔG= ΔH - T ΔS Kcal/mole Kd (µm) 3.4 ± 0.3 Thr3AA ± ± 10.0 The cognate substrate can indeed gain access and bind to the editing pocket in total contrast to the Double-Sieve Model.

20 Cognate post-transfer analog captured in the editing domain of archaeal ThrRS Ala94 Val45 Phe117 Ala82 Tyr120 W2 Tyr79 Lys121 First glimpse of cognate substrate in any editing domain of translational machinery Hussain et al. Proc. Natl. Acad. Sci. (USA) 2010, in press.

21 Functional positioning rather than steric exclusion is the key for the mechanism for proofreading Ser3AA Thr3AA W1 W2 W2 Tyr120 Lys121 Tyr120 Lys121 Resolution 1.86 Å for both structures Multiple data sets were collected for both the complexes Catalytic water (W1) is excluded in Pab-NTD-Thr3AA complex. Hussain et al. Proc. Natl. Acad. Sci. (USA) 2010, in press.

22 Ser Editing Site Functional Sieve Redefined Double-Sieve Model trna Thr Ser-tRNA Thr W1 Thr-tRNA Thr Ser-tRNA Thr trna Thr Catalytic Site Coarse Sieve Thr-tRNA Thr Thr-tRNA Thr Zn Thr Zn Zn Zn Ser Zn Val Ser Phe Phe Val Thr

23 Editing defecting complex can remove cognate amino acid L-Thr3AA analog at the editing site in K121M mutant L-Ser3AA analog at the editing site in Pab-NTD (wild type)

24 Conclusion A D-amino acid editing module coupled to a primordial aminoacyl-trna synthetase might have played a crucial role in enforcement and perpetuation of homochirality during translation. RNA mediated substrate-assisted catalysis is responsible for the proofreading reaction. Functional-positioning and not steric rejection is the key for Doublesieve mechanism. Ongoing work attempts to provide a structural model for editing defective synthetases leading to disease conditions.

25 Acknowledgments Shweta Dwivedi Tanweer Hussain Venu Kamarthapu Shobha Kruparani Financial Support: CSIR, India Wellcome Trust, UK for an ISRF in Biomedical Science Swarnajayanti Fellowship, DST, India

26 Thank you

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