Many Activities, One Structure: Functional Plasticity of Ribozyme Folds - PubMed (original) (raw)

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Many Activities, One Structure: Functional Plasticity of Ribozyme Folds

Matthew W L Lau et al. Molecules. 2016.

Abstract

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.

Keywords: fitness landscape; in vitro selection; ribozyme.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1

Fitness landscapes describe the relationship between the genotype and phenotype of an organism or sequence and the biochemical activity of a biopolymer. Fitness landscapes are very high-dimensional objects. For illustrative purposes, the genotype is reduced to a few dimensions. For this figure, the abscissa depicts a one-dimensional projection of all possible sequences (genetic distance) and the ordinate depicts the phenotypic fitness or biochemical activity. Evolution is an adaptive walk on the fitness landscape. (a) A smooth fitness landscape with many regions in which fitness varies monotonically with genetic change. A series of small or point mutations can lead without interruption from a local minimum (m) to a local maximum (M) of fitness; (b) A rugged fitness landscape, in which fitness varies unpredictably with genetic change. Adaptation is difficult for systems characterized by such surfaces, since many mutations will result in reduced fitness and mutants will be culled by natural selection (†) before a maximum can be achieved.

Figure 2

In vitro evolution of the co-enzyme independent, triple adenosine-mutant glmS metalloribozyme (_glmS_AAA) from the GlcN6P-dependent wild-type ribozyme (_glmS_WT) [37]. Global and active site structure of (a) _glmS_WT in green and (b) _glmS_AAA in light purple. Scissile phosphate is colored in black, and hydrogen bonding interactions are shown in dotted lines. Arrows depict the displacement of nucleobases (light purple) and the scissile phosphate (black) in the _glmS_AAA structure as compared to _glmS_WT.

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Many Activities, One Structure: Functional Plasticity of Ribozyme Folds - PubMed (original) (raw)