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.

PRMT5 是一种必需的精氨酸甲基转移酶，也是MTAP的治疗靶点-无效癌症。PRMT5 通过以前未定义的机制使用衔接蛋白进行底物募集。在这里，我们确定了三个已知底物适配器（CLNS1A、RIOK1 和 COPR5）之间共享的进化上保守的肽序列，并表明它对于与 PRMT5 的相互作用是必要和充分的。我们证明 PRMT5 使用包含共同结合基序的模块化接头蛋白进行底物募集，与其他酶类如激酶和 E3 连接酶相当。我们在结构上解决了与 PRMT5 的界面，并通过遗传扰动表明它是适配器招募的底物（包括剪接体、组蛋白和核糖体复合物）的甲基化所必需的。此外，该位点的破坏会影响 Sm 剪接体活性，导致内含子保留。MTAP -null 肿瘤细胞，因此是开发 PRMT5 治疗性抑制剂的位点。