Flexible binding of m6A reader protein YTHDC1 to its preferred RNA motif

TitleFlexible binding of m6A reader protein YTHDC1 to its preferred RNA motif
Publication TypeJournal Article
Year of Publication2019
AuthorsLi Y., Bedi R.K, Wiedmer L., Huang D., Śledź P., Caflisch A.
JournalJournal of Chemical Theory and Computation
Volume15
Issue12
Pagination7004-7014
Date Published2019 Dec 10
Type of ArticleResearch Article
ISSN1549-9626
Keywordsepitranscriptomics, m6A, m6A reader, molecular dynamics, RNA, RNA-Binding Proteins, X-ray crystallography
Abstract

-Methyladenosine (m6A) is the most prevalent chemical modification in human mRNAs. Its recognition by reader proteins enables many cellular functions, including splicing and translation of mRNAs. However, the binding mechanisms of m6A-containing RNAs to their readers are still elusive due to the unclear roles of m6A-flanking ribonucleotides. Here, we use a model system, YTHDC1 with its RNA motif 5'-GG(mA)CU-3', to investigate the binding mechanisms by atomistic simulations, X-ray crystallography, and isothermal titration calorimetry. The experimental data and simulation results show that m6A is captured by an aromatic cage of YTHDC1 and the 3' terminus nucleotides are stabilized by cation-π-π interactions, while the 5' terminus remains flexible. Notably, simulations of unbound RNA motifs reveal that the methyl group of m6A and the 5' terminus shift the conformational preferences of the oligoribonucleotide to the bound-like conformation, thereby facilitating the association process. The binding mechanisms may help in the discovery of chemical probes against m6A reader proteins.

DOI10.1021/acs.jctc.9b00987
pubindex

0250

Alternate JournalJ. Chem. Theory Comput.
PubMed ID31670957
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