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Structure. 2019 Oct 29. pii: S0969-2126(19)30347-8. doi: 10.1016/j.str.2019.10.006. [Epub ahead of print]

Capturing the Mechanism Underlying TOP mRNA Binding to LARP1.

Author information

1
Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, PA 15260, USA.
2
Department of Chemistry and Center for Nucleic Acids Science & Technology, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA.
3
Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, K1H 8L1 ON, Canada.
4
Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, PA 15260, USA. Electronic address: ajb190@pitt.edu.
5
Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, PA 15260, USA. Electronic address: durrantj@pitt.edu.

Abstract

The RNA-binding protein La-related protein 1 (LARP1) plays a central role in ribosome biosynthesis. Its C-terminal DM15 region binds the 7-methylguanosine (m7G) cap and 5' terminal oligopyrimidine (TOP) motif characteristic of transcripts encoding ribosomal proteins and translation factors. Under the control of mammalian target of rapamycin complex 1 (mTORC1), LARP1 regulates translation of these transcripts. Characterizing the dynamics of DM15-TOP recognition is essential to understanding this fundamental biological process. We use molecular dynamics simulations, biophysical assays, and X-ray crystallography to reveal the mechanism of DM15 binding to TOP transcripts. Residues C-terminal to the m7G-binding site play important roles in cap recognition. Furthermore, we show that the unusually static pocket that recognizes the +1 cytosine characteristic of TOP transcripts drives binding specificity. Finally, we demonstrate that the DM15 pockets involved in TOP-specific m7GpppC-motif recognition are likely druggable. Collectively, these studies suggest unique opportunities for further pharmacological development.

KEYWORDS:

DM15; LARP1; RNA-binding protein; TOP mRNA; X-ray crystallography; molecular dynamics; translation regulation

PMID:
31676287
DOI:
10.1016/j.str.2019.10.006

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