Molecular basis for substrate recruitment to the PRMT5 methylosome.
Molecular basis for substrate recruitment to the PRMT5 methylosome.
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DOI：
10.1016/j.molcel.2021.07.019
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发表时间：
2021-09-02
期刊：
影响因子：
16
通讯作者：
Sellers, William R.
中科院分区：
文献类型：
--
作者：
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.
PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP null cancers. PRMT5 utilizes 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 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 to 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. Further, 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. We present a unified model for substrate recruitment to the PRMT5 enzyme. Substrate adaptor proteins function in an exchangeable, and mutually exclusive, manner via the PBM binding site. This allows for specific methylation and regulation of distinct substrate classes using the same core enzyme.
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DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
10.5
作者：
Boutz PL;Bhutkar A;Sharp PA
通讯作者：
Sharp PA
DOI：
10.1007/978-3-319-46503-6_7
发表时间：
2017-01-01
期刊：
MACROMOLECULAR PROTEIN COMPLEXES: STRUCTURE AND FUNCTION
影响因子：
--
作者：
Antonysamy, Stephen
通讯作者：
Antonysamy, Stephen
影响因子：
5.3
作者：
Dacwag, Caroline S.;Ohkawa, Yasuyuki;Imbalzano, Anthony N.
通讯作者：
Imbalzano, Anthony N.