Abstract
BackgroundThe Argonaute protein is the core component of the RNA-induced silencing complex, playing the central role of cleaving the mRNA target. Visual inspection of static crystal structures already has enabled researchers to suggest conformational changes of Argonaute that might occur during RNA interference. We have taken the next step by performing an all-atom normal mode analysis of the Pyrococcus furiosus and Aquifex aeolicus Argonaute crystal structures, allowing us to quantitatively assess the feasibility of these conformational changes. To perform the analysis, we begin with the energy-minimized X-ray structures. Normal modes are then calculated using an all-atom molecular mechanics force field.ResultsThe analysis reveals low-frequency vibrations that facilitate the accommodation of RNA duplexes – an essential step in target recognition. The Pyrococcus furiosus and Aquifex aeolicus Argonaute proteins both exhibit low-frequency torsion and hinge motions; however, differences in the overall architecture of the proteins cause the detailed dynamics to be significantly different.ConclusionOverall, low-frequency vibrations of Argonaute are consistent with mechanisms within the current reaction cycle model for RNA interference.
Highlights
The Argonaute protein is the core component of the RNA-induced silencing complex, playing the central role of cleaving the mRNA target
root-mean-squared fluctuations (RMSFs) were calculated with Equation (4) at the ambient temperature of T = 300 K using the first 500 modes
0.54 Å, which is larger than the mean value of 0.33 Å in the Mid and PIWI domains
Summary
The Argonaute protein is the core component of the RNA-induced silencing complex, playing the central role of cleaving the mRNA target. We have taken the step by performing an all-atom normal mode analysis of the Pyrococcus furiosus and Aquifex aeolicus Argonaute crystal structures, allowing us to quantitatively assess the feasibility of these conformational changes. In RNAi, the RNase III family enzyme, called Dicer, cleaves the dsRNA into small interfering RNAs (siRNAs) of ~21 nt [4]. These small RNAs guide the silencing activities within the RNAinduced silencing complex (RISC). Structures of PAZ domains complexed with RNA demonstrated that siRNA recognition entails binding of the 3'-end by highly conserved aromatic residues [8,9]
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