Intra-domain cross-talk regulates serine-arginine protein kinase 1-dependent phosphorylation and splicing function of transformer 2β1

Michael A. Jamros, Brandon E. Aubol, Malik M. Keshwani, Zhaiyi Zhang, Stefan Stamm, Joseph A. Adams

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Transformer 2β1 (Tra2β1) is a splicing effector protein composed of a core RNA recognition motif flanked by two arginineserine-rich (RS) domains, RS1 and RS2. Although Tra2β1-dependent splicing is regulated by phosphorylation, very little is known about how protein kinases phosphorylate these two RS domains. We now show that the serine-arginine protein kinase-1 (SRPK1) is a regulator of Tra2β1 and promotes exon inclusion in the survival motor neuron gene 2 (SMN2). To understand how SRPK1 phosphorylates this splicing factor, we performed mass spectrometric and kinetic experiments. We found that SRPK1 specifically phosphorylates 21 serines in RS1, a process facilitated by a docking groove in the kinase domain. Although SRPK1 readily phosphorylates RS2 in a splice variant lacking the N-terminal RS domain (Tra2β3), RS1 blocks phosphorylation of these serines in the full-length Tra2β1. Thus, RS2 serves two new functions. First, RS2 positively regulates binding of the central RNA recognition motif to an exonic splicing enhancer sequence, a phenomenon reversed by SRPK1 phosphorylation on RS1. Second, RS2 enhances ligand exchange in the SRPK1 active site allowing highly efficient Tra2β1 phosphorylation. These studies demonstrate that SRPK1 is a regulator of Tra2β1 splicing function and that the individual RS domains engage in considerable cross-talk, assuming novel functions with regard to RNA binding, splicing, and SRPK1 catalysis.

Original languageEnglish
Pages (from-to)17269-17281
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number28
DOIs
StatePublished - Jul 10 2015

Bibliographical note

Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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