The Hammerhead Ribozyme: Structure, Catalysis, and Gene Regulation

Overview

Journal Prog Mol Biol Transl Sci

Specialty Molecular Biology

Date 2013 Oct 26

PMID 24156940

Citations 31

Authors

William G Scott

Lucas H Horan

Monika Martick

Affiliations

Soon will be listed here.

Abstract

The hammerhead ribozyme has long been considered a prototype for understanding RNA catalysis, but discrepancies between the earlier crystal structures of a minimal hammerhead self-cleaving motif and various biochemical investigations frustrated attempt to understand hammerhead ribozyme catalysis in terms of structure. With the discovery that a tertiary contact distal from the ribozyme's active site greatly enhances its catalytic prowess, and the emergence of new corresponding crystal structures of full-length hammerhead ribozymes, a unified understanding of catalysis in terms of the structure is now possible. A mechanism in which the invariant residue G12 functions as a general base, and the 2'-OH moiety of the invariant G8, itself forming a tertiary base pair with the invariant C3, is the general acid, appears consistent with both the crystal structure and biochemical experimental results. Originally discovered in the context of plant satellite RNA viruses, the hammerhead more recently has been found embedded in the 3'-untranslated region of mature mammalian mRNAs, suggesting additional biological roles in genetic regulation.

Citing Articles

Structural investigation of an RNA device that regulates PD-1 expression in mammalian cells.

Stagno J, Deme J, Dwivedi V, Lee Y, Lee H, Yu P Nucleic Acids Res. 2025; 53(5).

PMID: 40071935 PMC: 11897892. DOI: 10.1093/nar/gkaf156.

Strategies for detecting aminoacylation and aminoacyl-tRNA editing and in cells.

Watkins R, Kavoor A, Musier-Forsyth K Isr J Chem. 2025; 64(8-9).

PMID: 40066018 PMC: 11892019. DOI: 10.1002/ijch.202400009.

CHiTA: A scarless high-throughput pipeline for characterization of ribozymes.

McKinley L, Bevilacqua P Methods. 2024; 234:120-130.

PMID: 39662711 PMC: 11805615. DOI: 10.1016/j.ymeth.2024.12.007.

Recent Advances and Prospects of Nucleic Acid Therapeutics for Anti-Cancer Therapy.

Lee M, Lee M, Song Y, Kim S, Park N Molecules. 2024; 29(19).

PMID: 39407665 PMC: 11477775. DOI: 10.3390/molecules29194737.

A Newly Identified Peripheral Duplex Anchors and Stabilizes the MALAT1 Triplex.

Mwangi M, Yonkunas M, Ageeli A, McGovern-Gooch K, Yilmaz S, Baird N Biochemistry. 2024; 63(18):2280-2292.

PMID: 39190685 PMC: 11411715. DOI: 10.1021/acs.biochem.4c00156.

References

Ruffner D, Uhlenbeck O . Thiophosphate interference experiments locate phosphates important for the hammerhead RNA self-cleavage reaction. Nucleic Acids Res. 1990; 18(20):6025-9. PMC: 332400. DOI: 10.1093/nar/18.20.6025. View

Noller H, Hoffarth V, Zimniak L . Unusual resistance of peptidyl transferase to protein extraction procedures. Science. 1992; 256(5062):1416-9. DOI: 10.1126/science.1604315. View

Bassi G, Murchie A, Lilley D . The ion-induced folding of the hammerhead ribozyme: core sequence changes that perturb folding into the active conformation. RNA. 1996; 2(8):756-68. PMC: 1369413. View

de la Pena M, Gago S, Flores R . Peripheral regions of natural hammerhead ribozymes greatly increase their self-cleavage activity. EMBO J. 2003; 22(20):5561-70. PMC: 213784. DOI: 10.1093/emboj/cdg530. View

Fedor M . Comparative enzymology and structural biology of RNA self-cleavage. Annu Rev Biophys. 2009; 38:271-99. DOI: 10.1146/annurev.biophys.050708.133710. View

Murray J, Seyhan A, Walter N, Burke J, Scott W . The hammerhead, hairpin and VS ribozymes are catalytically proficient in monovalent cations alone. Chem Biol. 1998; 5(10):587-95. DOI: 10.1016/s1074-5521(98)90116-8. View

Carlyle J, Jamieson A, Gasser S, Clingan C, Arase H, Raulet D . Missing self-recognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors. Proc Natl Acad Sci U S A. 2004; 101(10):3527-32. PMC: 373496. DOI: 10.1073/pnas.0308304101. View

Rupert P, Massey A, Sigurdsson S, Ferre-DAmare A . Transition state stabilization by a catalytic RNA. Science. 2002; 298(5597):1421-4. DOI: 10.1126/science.1076093. View

de la Pena M, Garcia-Robles I . Ubiquitous presence of the hammerhead ribozyme motif along the tree of life. RNA. 2010; 16(10):1943-50. PMC: 2941103. DOI: 10.1261/rna.2130310. View

10.

Gardiner K, Marsh T, Pace N, Altman S . The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell. 1983; 35(3 Pt 2):849-57. DOI: 10.1016/0092-8674(83)90117-4. View

11.

Zhou J, Zhou D, Takagi Y, Kasai Y, Inoue A, Baba T . Existence of efficient divalent metal ion-catalyzed and inefficient divalent metal ion-independent channels in reactions catalyzed by a hammerhead ribozyme. Nucleic Acids Res. 2002; 30(11):2374-82. PMC: 117202. DOI: 10.1093/nar/30.11.2374. View

12.

De la Pena M, Flores R . An extra nucleotide in the consensus catalytic core of a viroid hammerhead ribozyme: implications for the design of more efficient ribozymes. J Biol Chem. 2001; 276(37):34586-93. DOI: 10.1074/jbc.M103867200. View

13.

Hammann C, Norman D, Lilley D . Dissection of the ion-induced folding of the hammerhead ribozyme using 19F NMR. Proc Natl Acad Sci U S A. 2001; 98(10):5503-8. PMC: 33242. DOI: 10.1073/pnas.091097498. View

14.

Murray J, Terwey D, Maloney L, Karpeisky A, Usman N, Beigelman L . The structural basis of hammerhead ribozyme self-cleavage. Cell. 1998; 92(5):665-73. DOI: 10.1016/s0092-8674(00)81134-4. View

15.

Mignone F, Gissi C, Liuni S, Pesole G . Untranslated regions of mRNAs. Genome Biol. 2002; 3(3):REVIEWS0004. PMC: 139023. DOI: 10.1186/gb-2002-3-3-reviews0004. View

16.

Martick M, Horan L, Noller H, Scott W . A discontinuous hammerhead ribozyme embedded in a mammalian messenger RNA. Nature. 2008; 454(7206):899-902. PMC: 2612532. DOI: 10.1038/nature07117. View

17.

Wang S, Karbstein K, Peracchi A, Beigelman L, Herschlag D . Identification of the hammerhead ribozyme metal ion binding site responsible for rescue of the deleterious effect of a cleavage site phosphorothioate. Biochemistry. 1999; 38(43):14363-78. DOI: 10.1021/bi9913202. View

18.

McKay D . Structure and function of the hammerhead ribozyme: an unfinished story. RNA. 1996; 2(5):395-403. PMC: 1369381. View

19.

Scott W, Finch J, Klug A . The crystal structure of an all-RNA hammerhead ribozyme: a proposed mechanism for RNA catalytic cleavage. Cell. 1995; 81(7):991-1002. DOI: 10.1016/s0092-8674(05)80004-2. View

20.

Hao L, Klein J, Nei M . Heterogeneous but conserved natural killer receptor gene complexes in four major orders of mammals. Proc Natl Acad Sci U S A. 2006; 103(9):3192-7. PMC: 1413923. DOI: 10.1073/pnas.0511280103. View