Molecular basis for substrate recruitment to the PRMT5 methylosome
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Abstract
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.
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Two complexes, Rpl12B-Rmt2 and Rpl7A-Fpr4, involving enzymes that introduce protein modifications such as arginine methylations or proline isomerizations, provide insight into mechanisms that expand the chemical diversity of ribosomal proteins at functional sites and possibly regulate translation.
“Two complexes, Rpl12B–Rmt2 and Rpl7A–Fpr4, involving enzymes that introduce protein modifications such as arginine methylations or proline isomerizations (47), provide insight into mechanisms that expand the chemical diversity of ribosomal proteins at functional sites (48) and possibly regulate translation (49).”
From Computed structures of core eukaryotic protein complexes (2021) · cites this paper as [47]
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Computed structures of core eukaryotic protein complexes
Humphreys, I. R., Pei, J., Baek, M., Krishnakumar, A., Anishchenko, I., Ovchinnikov, S., Zhang, J., Ness, T. J., Banjade, S., Bagde, S. R., et al. (2021) · Science · doi:10.1126/science.abm4805 · Cited by 542 · see citing works
- Authors
- Mulvaney, K. M., Blomquist, C., Acharya, N., Li, R., Ranaghan, M. J., O’Keefe, M., Rodriguez, D. J., Young, M. J., Kesar, D., Pal, D., Stokes, M., Nelson, A. J., Jain, S. S., Yang, A., Mullin-Bernstein, Z., Columbus, J., Bozal, F. K., Skepner, A., Raymond, D., LaRussa, S., McKinney, D. C., Freyzon, Y., Baidi, Y., Porter, D., Aguirre, A. J., Ianari, A., McMillan, B., & Sellers, W. R.
- Affiliations
- Broad Institute (US)
- Cell Signaling Technology (United States) (US)
- Tango Therapeutics (United States) (US)
- Corresponding author
- Sellers, William R.
- ORCID
- Mulvaney, Kathleen M.
- Acharya, Nischal
- Li, Ruitong
- Ranaghan, Matthew J.
- Rodriguez, Diego J.
- Young, Michael J.
- Kesar, Devishi
- Pal, Debjani
- Stokes, Matthew
- Nelson, Alissa J.
- Jain, Sidharth S.
- Yang, Annan
- Mullin-Bernstein, Zachary
- Bozal, Fazli K.
- Skepner, Adam
- Raymond, Donald
- LaRussa, Salvatore
- McKinney, David C.
- Baidi, Yossef
- Aguirre, Andrew J.
- Ianari, Alessandra
- McMillan, Brian
- Sellers, William R.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 81
- Issue
- 17
- Pages
- 3481-3495.e7
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC9016627
- OpenAlex
- W3190829687
- Cited by
- 93
- References
- 66
- Citations by year
- 2026: 10 · 2025: 32 · 2024: 12 · 2023: 19 · 2022: 15 · 2021: 5
- FWCI
- 4.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Broad Institute
- National Institutes of Health (NIH-R01)
- National Cancer Institute (F32CA232543, R01CA233626)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- PRMT5, methylosome, protein arginine methyltransferase, substrate recruitment, adaptor proteins, RIOK1, peptide binding motifs, protein-protein interfaces, spliceosome, Sm proteins, intron retention, histone methylation, PRMT5 inhibitors
- MeSH terms
- Animals, Cytoplasm, Female, Histones, Humans, Ion Channels, Male, Methylation, Mice, Nude, Nuclear Proteins, Peptides, Protein-Arginine N-Methyltransferases, Protein Binding, Protein Processing, Post-Translational, Protein Serine-Threonine Kinases, Spliceosomes, HCT116 Cells, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, HEK293 Cells
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