Capturing the Mechanism Underlying TOP mRNA Binding to LARP1
| Autor: | Jesse C. Kaminsky, Bruno D. Fonseca, Andrea J. Berman, Stephanie Mack, Kevin C. Cassidy, Jacob D. Durrant, Subha R. Das, Roni M. Lahr |
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| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
alpha-Helical Amino Acid Motifs Genetic Vectors Druggability Gene Expression RNA-binding protein mTORC1 Molecular Dynamics Simulation Crystallography X-Ray Ribosome Autoantigens Substrate Specificity 03 medical and health sciences Structural Biology Ribosomal protein Translational regulation Escherichia coli Humans Protein Interaction Domains and Motifs RNA Messenger Cloning Molecular Molecular Biology Binding selectivity 030304 developmental biology 0303 health sciences Ribosomal Protein S6 Binding Sites Base Sequence Guanosine Chemistry 030302 biochemistry & molecular biology LARP1 Recombinant Proteins Cell biology Ribonucleoproteins Thermodynamics Protein Binding |
| Zdroj: | Structure (London, England : 1993). 27(12) |
| ISSN: | 1878-4186 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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