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Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement

Argonaute (Ago) proteins and microRNAs (miRNAs) are central components in RNA interference, which is a key cellular mechanism for sequence-specific gene silencing. Despite intensive studies, molecular mechanisms of how Ago recognizes miRNA remain largely elusive. In this study, we propose a two-step...

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Autores principales: Jiang, Hanlun, Sheong, Fu Kit, Zhu, Lizhe, Gao, Xin, Bernauer, Julie, Huang, Xuhui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504477/
https://www.ncbi.nlm.nih.gov/pubmed/26181723
http://dx.doi.org/10.1371/journal.pcbi.1004404
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author Jiang, Hanlun
Sheong, Fu Kit
Zhu, Lizhe
Gao, Xin
Bernauer, Julie
Huang, Xuhui
author_facet Jiang, Hanlun
Sheong, Fu Kit
Zhu, Lizhe
Gao, Xin
Bernauer, Julie
Huang, Xuhui
author_sort Jiang, Hanlun
collection PubMed
description Argonaute (Ago) proteins and microRNAs (miRNAs) are central components in RNA interference, which is a key cellular mechanism for sequence-specific gene silencing. Despite intensive studies, molecular mechanisms of how Ago recognizes miRNA remain largely elusive. In this study, we propose a two-step mechanism for this molecular recognition: selective binding followed by structural re-arrangement. Our model is based on the results of a combination of Markov State Models (MSMs), large-scale protein-RNA docking, and molecular dynamics (MD) simulations. Using MSMs, we identify an open state of apo human Ago-2 in fast equilibrium with partially open and closed states. Conformations in this open state are distinguished by their largely exposed binding grooves that can geometrically accommodate miRNA as indicated in our protein-RNA docking studies. miRNA may then selectively bind to these open conformations. Upon the initial binding, the complex may perform further structural re-arrangement as shown in our MD simulations and eventually reach the stable binary complex structure. Our results provide novel insights in Ago-miRNA recognition mechanisms and our methodology holds great potential to be widely applied in the studies of other important molecular recognition systems.
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spelling pubmed-45044772015-07-17 Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement Jiang, Hanlun Sheong, Fu Kit Zhu, Lizhe Gao, Xin Bernauer, Julie Huang, Xuhui PLoS Comput Biol Research Article Argonaute (Ago) proteins and microRNAs (miRNAs) are central components in RNA interference, which is a key cellular mechanism for sequence-specific gene silencing. Despite intensive studies, molecular mechanisms of how Ago recognizes miRNA remain largely elusive. In this study, we propose a two-step mechanism for this molecular recognition: selective binding followed by structural re-arrangement. Our model is based on the results of a combination of Markov State Models (MSMs), large-scale protein-RNA docking, and molecular dynamics (MD) simulations. Using MSMs, we identify an open state of apo human Ago-2 in fast equilibrium with partially open and closed states. Conformations in this open state are distinguished by their largely exposed binding grooves that can geometrically accommodate miRNA as indicated in our protein-RNA docking studies. miRNA may then selectively bind to these open conformations. Upon the initial binding, the complex may perform further structural re-arrangement as shown in our MD simulations and eventually reach the stable binary complex structure. Our results provide novel insights in Ago-miRNA recognition mechanisms and our methodology holds great potential to be widely applied in the studies of other important molecular recognition systems. Public Library of Science 2015-07-16 /pmc/articles/PMC4504477/ /pubmed/26181723 http://dx.doi.org/10.1371/journal.pcbi.1004404 Text en © 2015 Jiang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jiang, Hanlun
Sheong, Fu Kit
Zhu, Lizhe
Gao, Xin
Bernauer, Julie
Huang, Xuhui
Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement
title Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement
title_full Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement
title_fullStr Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement
title_full_unstemmed Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement
title_short Markov State Models Reveal a Two-Step Mechanism of miRNA Loading into the Human Argonaute Protein: Selective Binding followed by Structural Re-arrangement
title_sort markov state models reveal a two-step mechanism of mirna loading into the human argonaute protein: selective binding followed by structural re-arrangement
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504477/
https://www.ncbi.nlm.nih.gov/pubmed/26181723
http://dx.doi.org/10.1371/journal.pcbi.1004404
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