Molecular basis for substrate recruitment to the PRMT5 methylosome
| Autor: | Andrew J. Aguirre, Nischal Acharya, Adam Skepner, Christa Blomquist, David C. McKinney, Michael J. Young, Meghan O’Keefe, Ruitong Li, Debjani Pal, Kathleen M. Mulvaney, Yelena Freyzon, Matthew E. Stokes, Fazli K. Bozal, Donald Raymond, Matthew J. Ranaghan, Devishi Kesar, Diego J. Rodriguez, Yossef Baidi, Annan Yang, William R. Sellers, Sidharth S. Jain, Dale Porter, Salvatore LaRussa, Alessandra Ianari, Josie Columbus, Zachary Mullin-Bernstein, Alissa J. Nelson, Brian J. McMillan |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Spliceosome Cytoplasm Protein-Arginine N-Methyltransferases Mice Nude Protein Serine-Threonine Kinases Methylation Article Ion Channels Histones Mice Cell Line Tumor Animals Humans Molecular Biology Peptide sequence Methylosome biology Protein arginine methyltransferase 5 Intron Intracellular Signaling Peptides and Proteins Signal transducing adaptor protein Nuclear Proteins Cell Biology HCT116 Cells Cell biology Histone HEK293 Cells RNA splicing biology.protein Spliceosomes Female Peptides Protein Processing Post-Translational Protein Binding |
| Zdroj: | Mol Cell |
| Popis: | PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5. |
| Databáze: | OpenAIRE |
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