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Many Activities, One Structure: Functional Plasticity of Ribozyme Folds

National Heart, Lung and Blood Institute, 50 South Drive, MSC 8012, Bethesda, MD 20892-8012, USA
Author to whom correspondence should be addressed.
Academic Editor: Sabine Müller
Molecules 2016, 21(11), 1570;
Received: 6 October 2016 / Revised: 12 November 2016 / Accepted: 14 November 2016 / Published: 18 November 2016
(This article belongs to the Special Issue Ribozymes and RNA Catalysis)
PDF [861 KB, uploaded 18 November 2016]


Catalytic RNAs, or ribozymes, are involved in a number of essential biological processes, such as replication of RNA genomes and mobile genetic elements, RNA splicing, translation, and RNA degradation. The function of ribozymes requires the formation of active sites decorated with RNA functional groups within defined three-dimensional (3D) structures. The genotype (sequence) of RNAs ultimately determines what 3D structures they adopt (as a function of their environmental conditions). These 3D structures, in turn, give rise to biochemical activity, which can further elaborate them by catalytic rearrangements or association with other molecules. The fitness landscape of a non-periodic linear polymer, such as RNA, relates its primary structure to a phenotype. Two major challenges in the analysis of ribozymes is to map all possible genotypes to their corresponding catalytic activity (that is, to determine their fitness landscape experimentally), and to understand whether their genotypes and three-dimensional structures can support multiple different catalytic functions. Recently, the combined results of experiments that employ in vitro evolution methods, high-throughput sequencing and crystallographic structure determination have hinted at answers to these two questions: while the fitness landscape of ribozymes is rugged, meaning that their catalytic activity cannot be optimized by a smooth trajectory in sequence space, once an RNA achieves a stable three-dimensional fold, it can be endowed with distinctly different biochemical activities through small changes in genotype. This functional plasticity of highly structured RNAs may be particularly advantageous for the adaptation of organisms to drastic changes in selective pressure, or for the development of new biotechnological tools. View Full-Text
Keywords: ribozyme; in vitro selection; fitness landscape ribozyme; in vitro selection; fitness landscape

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Lau, M.W.; Ferré-D’Amaré, A.R. Many Activities, One Structure: Functional Plasticity of Ribozyme Folds. Molecules 2016, 21, 1570.

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