A common RNA loop motif as a docking module and its function in the hammerhead ribozyme

Here I present a three-dimensional model of a novel element of RNA tertiary structure. A common loop motif composed of adjacent, sheared GA and AN non-canonical base pairs is proposed to form long-range tertiary interactions with other RNA residues. The widespread distribution of this GA/AN docking module suggests that the putative long-range docking interaction plays an important role in specifying the tertiary structure of large RNAs, and perhaps the quaternary structure of some intermolecular RNA−RNA interactions. Application of this docking module hypothesis to the hammerhead ribozyme provides crucial constraints for the calculation of three-dimensional models of its self-cleaving conformation.

1. Chastain, M. & Tinoco, I., Jr., Structural elements in RNA. Prog. Nucleic. Acid Res. molec. Biol. 41, 131−177 1991). | ISI | ChemPort |
2. Holbrook, S.R., Sussman, J.L., Warrant, R.W. & Kim, S.-H. Crystal structure of yeast phenylalanine transfer RNA II. Structural features and functional implications. J. molec. Biol. 123, 631−660 (1978). | PubMed | ISI | ChemPort |
3. Jack, A., Ladner, J.E. & Klug, A. Crystallographic refinement of yeast phenylalanine transfer RNA at 2.5 Å resolution. J. molec. Biol. 108, 619−649 (1976). | PubMed | ISI | ChemPort |
4. Westhof, E., Dumas, P. & Moras, D. Crystallographic refinement of yeast aspartic acid transfer RNA. J. molec. Biol. 184, 119−145 (1985). | PubMed | ISI | ChemPort |
5. Biou, V., Yaremchuk, A., Tukalo, M. & Cusack, S. The 2.9 Å crystal structure of T. thermophilus seryl-tRNA synthetase complexed with tRNA^Ser. Science 263, 1404−1410 (1994). | PubMed | ISI | ChemPort |
6. Rould, M.A., Perona, J.J. & Steitz, T.A. Structural basis of anticodon loop recognition by glutaminyl-tRNA synthetase. Nature 352, 213−218 (1991). | Article | PubMed | ISI | ChemPort |
7. Cavarelli, J., Rees, B., Ruff, M., Thierry, J.C. & Moras, D. Yeast tRNA^Asp recognition by its cognate class II aminoacyl-tRNA synthetase. Nature 362, 181−184 (1993). | Article | PubMed | ISI | ChemPort |
8. Basavappa, R. & Sigler, P. B. The 3 Å crystal structure of yeast initiator tRNA: functional implications in initiator/elongator discrimination. EMBO J. 10, 3105−3111 (1991). | PubMed | ISI | ChemPort |
9. Varani, G., Cheong, C. & Tinoco, I., Jr. Structure of an unusually stable RNA hairpin. Biochemistry. 30, 3280−3289 (1991). | PubMed | ISI | ChemPort |
10. Heus, H. & Pardi, A. Structural features that give rise to the unusual stability of RNA hairpins containing GNRA loops. Science 253, 191−194 (1991). | PubMed | ISI | ChemPort |
11. Wimberly, B., Varani, G. & Tinoco, I. Jr. The conformation of loop E of eukaryotic 5S ribosomal RNA. Biochemistry. 32, 1078−1087 (1993). | PubMed | ISI | ChemPort |
12. Szewczak, A.A., Moore, P.B., Chang, Y.L. & Wool, I.G. The conformation of the sarcin/ricin loop from 28S ribosomal RNA. Proc. natn. Acad. Sci. U.S.A. 90, 9581−9585 (1993). | ChemPort |
13. SantaLucia, J. & Turner, D.H. Structure of (rGGC(GA)GCC)₂ in solution from NMR and restrained molecular dynamics. Biochemistry. 32, 12612−12623 (1993). | PubMed | ISI | ChemPort |
14. Leclerc, F., Cedergren, R. & Ellington, A.D. A three-dimensional model of the Rev-binding element of HIV-I derived from analyses of aptamers. Nature struct. Biol. 1, 293−300 (1994). | PubMed | ISI | ChemPort |
15. Branch, A. D., Benenfeld, B. J. & Robertson, H. D. Ultraviolet light-induced crosslinking reveals a unique region of local tertiary structure in potato spindle tuber viroid and HeLa 5S RNA. Proc. natn. Acad. Sci. U.S.A. 82, 6590−6594 (1985). | ChemPort |
16. Keese, P. & Symons, R. H. Domains in viroids: evidence of intermolecular RNA rearrangements and their contribution to viroid evolution. Proc. natn. Acad. Sci. U.S.A. 82, 4582−4586 (1985). | ChemPort |
17. Gutell, R. R., Larsen, N. & Woese, C. R. Lessons from an evolving rRNA: 16S and 23S rRNA structures from a comparative perspective. Microbiol. Rev. 58, 10−26 (1994). | PubMed | ISI | ChemPort |
18. Nierhaus, K. H., Schilling-Bartetzko, S. & Twardowski, T. The two main states of the elongating ribosome and the role of the alpha-sarcin stem-loop structure of 23S RNA. Biochimie 74, 403−410 (1992). | Article | PubMed | ISI | ChemPort |
19. Wool, I.G., Gluck, A. & Endo, Y. Ribotoxin recognition of ribosomal RNA and a proposal for the mechanism of translocation. Trends biochem. Sci. 17, 266−269 (1992). | Article | PubMed | ISI | ChemPort |
20. Gluck, A., Endo, Y. & Wool, I.G. The ribosomal RNA identity elements for ricin and for alpha-sarcin: mutations in the putative CG pair that closes a GAGA tetraloop. Nucleic Acids Res. 22, 321−324 (1994). | PubMed | ISI | ChemPort |
21. Butcher, S.E. & Burke, J.M. A photo-cross-linkable tertiary structure motif found in functionally distinct RNA molecules is essential for catalytic function of the hairpin ribozyme. Biochemistry. 33, 992−999 (1994). | PubMed | ISI | ChemPort |
22. Berzal-Herranz, A., Joseph, S., Chowrira, B.M., Butchet, S.E. & Burke, J.M. Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J. 12, 2567−2573 (1993). | PubMed | ChemPort |
23. Aagaard, C. & Douthwaite, S. Requirement for a conserved, tertiary interaction in the core of 23S ribosomal RNA. Proc. natn Acad. Sci. U.S.A. 91, 2989−2993 (1994). | ChemPort |
24. Wise, J. Guides to the heart of the spliceosome. Science 262, 1978−1979 (1993). | PubMed | ISI | ChemPort |
25. Pyle, A.M. Ribozymes: a distinct class of metalloenzymes. Science 261, 709−714 (1993). | PubMed | ISI | ChemPort |
26. Bratty, J., Chartrand, P., Ferbeyre, G. & Cedergren, R. The hammerhead RNA domain, a model ribozyme. Biochim. biophys. Acta 1216, 345−359 (1993). | Article | PubMed | ISI | ChemPort |
27. Pease, A.C. & Wemmer, D.E. Characterization of the secondary structure and melting of a self-cleaved RNA hammerhead domain by ¹H NMR spectroscopy. Biochemistry. 29, 9039−9046 (1990). | PubMed | ISI | ChemPort |
28. Heus, H.A. & Pardi, A. Nuclear magnetic resonance studies of the hammerhead ribozyme domain. Secondary structure formation and magnesium ion dependence. J. molec. Biol. 217, 113−124 (1991). | PubMed | ISI | ChemPort |
29. Pley, H.W., Lindes, D.S., DeLuca-Flaherty, C. & McKay, D.B. Crystals of a hammerhead ribozyme. J. biol. Chem. 268, 19658−9658 (1993).
30. Kim, R. et.al. High-resolution crystals and preliminary X-ray diffraction studies of a catalytic RNA. Acta crystallogr. D50, 290−292 (1994). | ChemPort |
31. Major, F., Turcotte, M., Gautheret, D., Lapalme, G., Fillion, E. & Cedergren, R. The combination of symbolic and numerical computation for three-dimensional modelling of RNA. Science 253, 1255−1260 (1991). | PubMed | ISI | ChemPort |
32. Gautheret, D., Major, F. & Cedergren, R. Modelling the three-dimensional structure of RNA using discrete nucleotide conformational sets. J. molec. Biol. 229, 1049−1064 (1993). | Article | PubMed | ISI | ChemPort |
33. Brünger, A.T. X-PLOR: a system for crystallography and NMR. (New Haven, Yale University Press;) (1992).
34. Mei, H.Y., Kaaref, T.W. & Bruice, T.C. A computational approach to the mechanism of self-cleavage of hammerhead RNA. Proc. natn Acad Sci. U.S.A. 86, 9727−9731 (1989). | ChemPort |
35. Woisard, A., Favre, A., Clivio, P. & Fourrey, J.-L. Hammerhead ribozyme tertiary folding: intrinsic photolabeling studies. J. Am. chem. Soc. 114, 10072−10074 (1992). | ISI | ChemPort |
36. Fu, D.-J., Rajur, S.B. & McLaughlin, L.W. Importance of specific guanosine N⁷-nitrogens and purine amino groups for efficient cleavage by a hammerhead ribozyme. Biochemistry 32, 10629−10637 (1993). | PubMed | ISI | ChemPort |
37. Fu, D.-J. & McLaughlin, L.W. Importance of specific adenosine N⁷-nitrogens for efficient cleavage by a hammerhead ribozyme. A model for magnesium binding. Biochemistry 31, 10941−10949 (1992). | PubMed | ISI | ChemPort |
38. Dahm, S.C., Derrick, W.B. & Uhlenbeck, O.C. Evidence for the role of solvated metal hydroxide in the hammerhead cleavage mechanism. Biochemistry 32, 13040−13045 (1993). | PubMed | ISI | ChemPort |
39. Ruffner, D.E. & Uhlenbeck, O.C. Thiophosphate interference experiments locate phosphates important for the hammerhead RNA self-cleavage reaction. Nucleic Acids Res, 18, 6025−6029 (1990). | PubMed | ISI | ChemPort |
40. Slim, G. & Gait, M.J. Configurationally defined phosphorothioate-containing oligoribonucleotides in the study of the mechanism of cleavage of hammerhead ribozymes. Nucleic. Acids Res. 19, 1183−1188 (1991). | PubMed | ISI | ChemPort |
41. Dahm, S.C. & Uhlenbeck, O.C. Role of divalent metal ions in the hammerhead RNA cleavage reaction. Biochemistry 30, 9464−9469 (1991). | PubMed | ISI | ChemPort |
42. Hertel, K.J. et al. Numbering system for the hammerhead. Nucleic Acids Res. 20, 3252 (1992). | PubMed | ISI | ChemPort |
43. Ruffner, D.E., Stormo, G.D. & Uhlenbeck, O.C. Sequence requirements of the hammerhead RNA self-cleavage reaction. Biochemistry 29, 10695−10702 (1990). | PubMed | ISI | ChemPort |

	Top

	Top