Understanding the core of RNA interference: The dynamic aspects of Argonaute-mediated processes

Lizhe Zhu; Hanlun Jiang; Fu Kit Sheong; Xuefeng Cui; Yanli Wang; Xin Gao; Xuhui Huang

doi:10.1016/j.pbiomolbio.2016.09.008

Understanding the core of RNA interference: The dynamic aspects of Argonaute-mediated processes

Prog Biophys Mol Biol. 2017 Sep:128:39-46. doi: 10.1016/j.pbiomolbio.2016.09.008. Epub 2016 Sep 30.

Authors

Lizhe Zhu¹, Hanlun Jiang², Fu Kit Sheong³, Xuefeng Cui⁴, Yanli Wang⁵, Xin Gao⁴, Xuhui Huang⁶

Affiliations

¹ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
² Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Bioengineering Graduate Program, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
³ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
⁴ King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, Thuwal, 23955, Saudi Arabia.
⁵ Laboratory of Non-Coding RNA, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
⁶ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Center of Systems Biology and Human Health, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong; Bioengineering Graduate Program, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong. Electronic address: Xin.Gao@kaust.edu.sa.

PMID: 27697475
DOI: 10.1016/j.pbiomolbio.2016.09.008

Abstract

At the core of RNA interference, the Argonaute proteins (Ago) load and utilize small guide nucleic acids to silence mRNAs or cleave foreign nucleic acids in a sequence specific manner. In recent years, based on extensive structural studies of Ago and its interaction with the nucleic acids, considerable progress has been made to reveal the dynamic aspects of various Ago-mediated processes. Here we review these novel insights into the guide-strand loading, duplex unwinding, and effects of seed mismatch, with a focus on two representative Agos, the human Ago 2 (hAgo2) and the bacterial Thermus thermophilus Ago (TtAgo). In particular, comprehensive molecular simulation studies revealed that although sharing similar overall structures, the two Agos have vastly different conformational landscapes and guide-strand loading mechanisms because of the distinct rigidity of their L1-PAZ hinge. Given the central role of the PAZ motions in regulating the exposure of the nucleic acid binding channel, these findings exemplify the importance of protein motions in distinguishing the overlapping, yet distinct, mechanisms of Ago-mediated processes in different organisms.

Keywords: Argonaute; Enhanced sampling; Kinetics; Markov-state-models; Mechanism; Molecular dynamics simulation; Protein motions; Protein-DNA/RNA docking; RNA interference.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Argonaute Proteins / metabolism*
Humans
RNA Interference*
Thermus thermophilus / genetics
Thermus thermophilus / metabolism

Substances

Argonaute Proteins