<br>细胞类型特异性调节剂 RBPMS 通过高阶寡聚化和与其他剪接调节剂的异型相互作用来切换选择性剪接,Nucleic Acids Research

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细胞类型特异性调节剂 RBPMS 通过高阶寡聚化和与其他剪接调节剂的异型相互作用来切换选择性剪接
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2023-08-07 , DOI: 10.1093/nar/gkad652
Yi Yang ₁ , Giselle C Lee ₁ , Erick Nakagaki-Silva ₁ , Yuling Huang ₁ , Matthew Peacey ₁ , Ruth Partridge ₁ , Clare Gooding ₁ , Christopher W J Smith ₁

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替代性前 mRNA 剪接决策由 RNA 结合蛋白 (RBP) 调节，RBP 可以激活或抑制受调节的剪接位点。抑制性 RBP 通常利用多价相互作用来稳定地结合靶 RNA。多价性可以通过同聚寡聚化和与其他 RBP 的异聚相互作用来实现，通常由本质无序区域 (IDR) 介导，并通过拥有多个 RNA 结合域来实现。细胞特异性剪接决策通常涉及广泛表达的 RBP 的作用，这些 RBP 能够多价结合在目标外显子周围，但在缺乏细胞特异性调节因子的情况下不起作用。为了解决细胞特异性调节因子如何在选择性剪接调节中与组成型 RBP 协作，我们使用了平滑肌特异性调节因子 RBPMS。重组 RBPMS 足以通过阻止 ATP 依赖性剪接复合物的组装，在无细胞测定中赋予平滑肌细胞特异性 Tpm1 外显子 3 选择性剪接。该活性依赖于 C 端 IDR，促进动态高阶自组装、与多价 RNA 的协同结合以及与广泛表达的剪接共调节因子（包括 MBNL1 和 RBFOX2）的相互作用，从而允许稳定的细胞特异性调节复合物的协同组装。

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Cell-type specific regulator RBPMS switches alternative splicing via higher-order oligomerization and heterotypic interactions with other splicing regulators

Alternative pre-mRNA splicing decisions are regulated by RNA binding proteins (RBPs) that can activate or repress regulated splice sites. Repressive RBPs typically harness multivalent interactions to bind stably to target RNAs. Multivalency can be achieved by homomeric oligomerization and heteromeric interactions with other RBPs, often mediated by intrinsically disordered regions (IDRs), and by possessing multiple RNA binding domains. Cell-specific splicing decisions often involve the action of widely expressed RBPs, which are able to bind multivalently around target exons, but without effect in the absence of a cell-specific regulator. To address how cell-specific regulators can collaborate with constitutive RBPs in alternative splicing regulation, we used the smooth-muscle specific regulator RBPMS. Recombinant RBPMS is sufficient to confer smooth muscle cell specific alternative splicing of Tpm1 exon 3 in cell-free assays by preventing assembly of ATP-dependent splicing complexes. This activity depends upon a C-terminal IDR that facilitates dynamic higher-order self-assembly, cooperative binding to multivalent RNA and interactions with widely expressed splicing co-regulators, including MBNL1 and RBFOX2, allowing cooperative assembly of stable cell-specific regulatory complexes.

更新日期：2023-08-07

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