Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing

The RNA recognition motif (RRM) binds to nucleic acids as well as proteins. More than one such domain is found in the pre-mRNA processing hnRNP proteins. While the mode of RNA recognition by RRMs is known, the molecular basis of their protein interaction remains obscure. Here we describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2. We demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SETD2 insert their side chains in hydrophobic pockets formed by hnRNP L RRM2. Notably, the structure also highlights that RRM2 can form a ternary complex with SETD2 and RNA. Remarkably, mutating the leucine pair in SETD2 also results in its reduced interaction with other hnRNPs. Importantly, the similarity that the mode of SETD2-hnRNP L interaction shares with other related protein-protein interactions reveals a conserved design by which splicing regulators interact with one another. Interaction between SETD2 and hnRNP L has previously been shown to be implicated in coupling gene transcription and mRNA processing. Here the authors elucidate the molecular basis of this functional interaction, showing that the RRM domain of hnRNP L possesses non-overlapping binding interfaces for engaging RNA and SETD2.

Automated summary

The paper describes the interaction between hnRNP L and SETD2, revealing their binding mechanism. The study demonstrates that a leucine pair in SETD2 inserts their side chains in hydrophobic pockets formed by hnRNP L RRM2 for interaction to occur, highlighting the importance of this binding interaction. The similarity in the mode of SETD2-hnRNP L interaction with other related protein-protein interactions suggests a conserved design for splicing regulators to interact with one another.