Molecular basis for substrate recruitment to the PRMT5 methylosome.
Animals
Cell Line, Tumor
Cytoplasm
/ metabolism
Female
HCT116 Cells
HEK293 Cells
Histones
/ metabolism
Humans
Intracellular Signaling Peptides and Proteins
/ metabolism
Ion Channels
/ metabolism
Male
Methylation
Mice
Mice, Nude
Nuclear Proteins
/ metabolism
Peptides
/ genetics
Protein Binding
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases
/ metabolism
Protein-Arginine N-Methyltransferases
/ genetics
Spliceosomes
/ metabolism
CDKN2A
COPR5
MTAP
PRMT5
RIOK1
Sm protein
arginine methylation
histone
pICln
splicing
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
02 09 2021
02 09 2021
Historique:
received:
11
02
2021
revised:
07
06
2021
accepted:
14
07
2021
pubmed:
7
8
2021
medline:
21
4
2022
entrez:
6
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34358446
pii: S1097-2765(21)00588-8
doi: 10.1016/j.molcel.2021.07.019
pmc: PMC9016627
mid: NIHMS1782553
pii:
doi:
Substances chimiques
CLNS1A protein, human
0
COPRS protein, human
0
Histones
0
Intracellular Signaling Peptides and Proteins
0
Ion Channels
0
Nuclear Proteins
0
Peptides
0
PRMT2 protein, human
EC 2.1.1.319
PRMT5 protein, human
EC 2.1.1.319
Protein-Arginine N-Methyltransferases
EC 2.1.1.319
Protein Serine-Threonine Kinases
EC 2.7.11.1
RIOK1 protein, human
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3481-3495.e7Subventions
Organisme : NCI NIH HHS
ID : F32 CA232543
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233626
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Materials related to this article are in a provisional patent application by the Broad Institute. W.R.S. is a board or scientific advisory board (SAB) member and holds equity in Peloton Therapeutics, Ideaya Biosciences, Civetta Therapeutics, and Bluebird bio; has consulted for Array, Astex, Dynamo Therapeutics, Ipsen, Merck Pharmaceuticals, PearlRiver Therapeutics, Sanofi, Scorpion Therapeutics, and Servier; and receives research funding from Pfizer Pharmaceuticals, Merck Pharmaceuticals, Ideaya Biosciences, and Deerfield Management. B.J.M. is an employee and equity holder of Tango Therapeutics. D. Porter is an employee and equity holder of Cedilla Therapeutics. A.J.A. has consulted for Oncorus Inc., Arrakis Therapeutics, and Merck & Company and has research funding from Mirati Therapeutics and Deerfield Management.
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