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

Saikat Bhattacharya, Suman Wang, Divya Reddy, Siyuan Shen, Ying Zhang, Ning Zhang, Hua Li, Michael P. Washburn, Laurence Florens, Yunyu Shi, Jerry L. Workman () and Fudong Li ()
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Saikat Bhattacharya: Stowers Institute for Medical Research
Suman Wang: Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China
Divya Reddy: Stowers Institute for Medical Research
Siyuan Shen: Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China
Ying Zhang: Stowers Institute for Medical Research
Ning Zhang: Stowers Institute for Medical Research
Hua Li: Stowers Institute for Medical Research
Michael P. Washburn: University of Kansas Medical Center
Laurence Florens: Stowers Institute for Medical Research
Yunyu Shi: Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China
Jerry L. Workman: Stowers Institute for Medical Research
Fudong Li: Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26799-3

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