Publication details
Recognition of N6-Methyladenosine by the YTHDC1 YTH Domain Studied by Molecular Dynamics and NMR Spectroscopy: The Role of Hydration
| Authors | |
|---|---|
| Year of publication | 2021 |
| Type | Article in Periodical |
| Magazine / Source | Journal of Physical Chemistry B |
| MU Faculty or unit | |
| Citation | |
| Web | https://doi.org/10.1021/acs.jpcb.1c03541 |
| Doi | http://dx.doi.org/10.1021/acs.jpcb.1c03541 |
| Keywords | Genetics; Monomers; Molecules; Protein structure; Chemical calculations |
| Description | The YTH domain of YTHDC1 belongs to a class of protein "readers", recognizing the N6-methyladenosine (m(6)A) chemical modification in mRNA. Static ensemble-averaged structures revealed details of N6-methyl recognition via a conserved aromatic cage. Here, we performed molecular dynamics (MD) simulations along with nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC) to examine how dynamics and solvent interactions contribute to the m(6)A recognition and negative selectivity toward an unmethylated substrate. The structured water molecules surrounding the bound RNA and the methylated substrate's ability to exclude bulk water molecules contribute to the YTH domain's preference for m(6)A. Intrusions of bulk water deep into the binding pocket disrupt binding of unmethylated adenosine. The YTHDC1's preference for the 5'-Gm(6)A-3' motif is partially facilitated by a network of water-mediated interactions between the 2amino group of the guanosine and residues in the m(6)A binding pocket. The 5'-Im(6)A-3' (where I is inosine) motif can be recognized too, but disruption of the water network lowers affinity. The D479A mutant also disrupts the water network and destabilizes m(6)A binding. Our interdisciplinary study of the YTHDC1 protein-RNA complex reveals an unusual physical mechanism by which solvent interactions contribute toward m(6)A recognition. |
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