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Molecular basis for substrate recruitment to the PRMT5 methylosome.
Mulvaney, Kathleen M; Blomquist, Christa; Acharya, Nischal; Li, Ruitong; Ranaghan, Matthew J; O'Keefe, Meghan; Rodriguez, Diego J; Young, Michael J; Kesar, Devishi; Pal, Debjani; Stokes, Matthew; Nelson, Alissa J; Jain, Sidharth S; Yang, Annan; Mullin-Bernstein, Zachary; Columbus, Josie; Bozal, Fazli K; Skepner, Adam; Raymond, Donald; LaRussa, Salvatore; McKinney, David C; Freyzon, Yelena; Baidi, Yossef; Porter, Dale; Aguirre, Andrew J; Ianari, Alessandra; McMillan, Brian; Sellers, William R.
Afiliação
  • Mulvaney KM; Broad Institute, Cambridge, MA, USA.
  • Blomquist C; Broad Institute, Cambridge, MA, USA.
  • Acharya N; Broad Institute, Cambridge, MA, USA.
  • Li R; Broad Institute, Cambridge, MA, USA.
  • Ranaghan MJ; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
  • O'Keefe M; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
  • Rodriguez DJ; Broad Institute, Cambridge, MA, USA.
  • Young MJ; Broad Institute, Cambridge, MA, USA.
  • Kesar D; Broad Institute, Cambridge, MA, USA.
  • Pal D; Broad Institute, Cambridge, MA, USA.
  • Stokes M; Cell Signaling Technologies, Danvers, MA, USA.
  • Nelson AJ; Cell Signaling Technologies, Danvers, MA, USA.
  • Jain SS; Broad Institute, Cambridge, MA, USA.
  • Yang A; Tango Therapeutics, Cambridge, MA, USA.
  • Mullin-Bernstein Z; Broad Institute, Cambridge, MA, USA.
  • Columbus J; Broad Institute, Cambridge, MA, USA.
  • Bozal FK; Broad Institute, Cambridge, MA, USA.
  • Skepner A; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
  • Raymond D; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
  • LaRussa S; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
  • McKinney DC; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA.
  • Freyzon Y; Broad Institute, Cambridge, MA, USA.
  • Baidi Y; Broad Institute, Cambridge, MA, USA.
  • Porter D; Broad Institute, Cambridge, MA, USA; Cedilla Therapeutics, Cambridge, MA, USA.
  • Aguirre AJ; Broad Institute, Cambridge, MA, USA; Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Ianari A; Broad Institute, Cambridge, MA, USA.
  • McMillan B; Center for the Development of Therapeutics, Broad Institute, Cambridge, MA, USA; Tango Therapeutics, Cambridge, MA, USA.
  • Sellers WR; Broad Institute, Cambridge, MA, USA; Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Electronic address: wsellers@broadinstitute.org.
Mol Cell ; 81(17): 3481-3495.e7, 2021 09 02.
Article em En | MEDLINE | ID: mdl-34358446
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteína-Arginina N-Metiltransferases Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteína-Arginina N-Metiltransferases Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article