Search

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. [Display omitted] • Identified PRMT5 binding motif (PBM) for recruitment of substrate adaptors to PRMT5 • The PBM is required for methylation of select PRMT5 substrates • Mutation of the PBM leads to decreased Sm complex activity and detained introns • Mutation of the PBM leads to decreased viability in cancer cells Mulvaney et al. identify how substrate adaptor proteins recruit substrates to PRMT5 for methylation, akin to F box proteins and E3 ligases. Substrate recruitment motifs for protein arginine methyltransferases are largely uncharacterized. Moreover, this interaction site is required for select substrate methylation and viability in cancer cells. [ABSTRACT FROM AUTHOR]