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

Author

Listed:
  • 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
    Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, 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
    Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, 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
    Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, 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
    Ministry of Education Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science and Technology of China)

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.

Suggested Citation

  • Saikat Bhattacharya & Suman Wang & Divya Reddy & Siyuan Shen & Ying Zhang & Ning Zhang & Hua Li & Michael P. Washburn & Laurence Florens & Yunyu Shi & Jerry L. Workman & Fudong Li, 2021. "Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26799-3
    DOI: 10.1038/s41467-021-26799-3
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    References listed on IDEAS

    as
    1. Eric T. Wang & Rickard Sandberg & Shujun Luo & Irina Khrebtukova & Lu Zhang & Christine Mayr & Stephen F. Kingsmore & Gary P. Schroth & Christopher B. Burge, 2008. "Alternative isoform regulation in human tissue transcriptomes," Nature, Nature, vol. 456(7221), pages 470-476, November.
    2. Saikat Bhattacharya & Michaella J. Levy & Ning Zhang & Hua Li & Laurence Florens & Michael P. Washburn & Jerry L. Workman, 2021. "The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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