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Molecular basis for substrate recruitment to the PRMT5 methylosome

ABSTRACT: Molecular basis for substrate recruitment to the PRMT5 methylosome

PROVIDER: PRJNA736940 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14785630_1.fastq.gz	Fastqsanger.gz
	SRR14785630_2.fastq.gz	Fastqsanger.gz
	SRR14785631_1.fastq.gz	Fastqsanger.gz
	SRR14785631_2.fastq.gz	Fastqsanger.gz
	SRR14785632_1.fastq.gz	Fastqsanger.gz

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Molecular basis for substrate recruitment to the PRMT5 methylosome

Project description: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 ribosome assembly complexes. Further, disruption of this site affects Sm spliceosome stability and activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface leads to a hypomorphic decrease in growth of MTAP null tumor cells in vitro and in vivo, and is thus a novel site for development of therapeutic inhibitors of PRMT5.

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Molecular basis for substrate recruitment to the PRMT5 methylosome.

Project description: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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