Molecular interactions connecting the function of the serine-arginine–rich protein SRSF1 to protein phosphatase 1

Splicing generates many mRNA strands from a single precursor mRNA, expanding the proteome and enhancing intracellular diversity. Both initial assembly and activation of the spliceosome require an essential family of splicing factors called serine-arginine (SR) proteins. Protein phosphatase 1 (PP1) r...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-10, Vol.293 (43), p.16751-16760
Main Authors: Aubol, Brandon E., Serrano, Pedro, Fattet, Laurent, Wüthrich, Kurt, Adams, Joseph A.
Format: Article
Language:English
Subjects:
Alternative Splicing
Amino Acid Sequence
Arginine - chemistry
Arginine - genetics
Arginine - metabolism
Crystallography, X-Ray
enzyme kinetics
enzyme mutation
Enzymology
Humans
phosphatase
Phosphorylation
Protein Binding
Protein Conformation
protein kinase
Protein Processing, Post-Translational
Receptors, Neuropeptide Y - chemistry
Receptors, Neuropeptide Y - genetics
Receptors, Neuropeptide Y - metabolism
Ribonucleoside Diphosphate Reductase
Sequence Homology
Serine - chemistry
Serine - genetics
Serine - metabolism
Serine-Arginine Splicing Factors - chemistry
Serine-Arginine Splicing Factors - genetics
Serine-Arginine Splicing Factors - metabolism
Spliceosomes
Tumor Suppressor Proteins - chemistry
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary:Splicing generates many mRNA strands from a single precursor mRNA, expanding the proteome and enhancing intracellular diversity. Both initial assembly and activation of the spliceosome require an essential family of splicing factors called serine-arginine (SR) proteins. Protein phosphatase 1 (PP1) regulates the SR proteins by controlling phosphorylation of a C-terminal arginine-serine–rich (RS) domain. These modifications are vital for the subcellular localization and mRNA splicing function of the SR protein. Although PP1 has been shown to dephosphorylate the prototype SR protein splicing factor 1 (SRSF1), the molecular nature of this interaction is not understood. Here, using NMR spectroscopy, we identified two electrostatic residues in helix α2 and a hydrophobic residue in helix α1 in the RNA recognition motif 1 (RRM1) of SRSF1 that constitute a binding surface for PP1. Substitution of these residues dissociated SRSF1 from PP1 and enhanced phosphatase activity, reducing phosphorylation in the RS domain. These effects lead to shifts in alternative splicing patterns that parallel increases in SRSF1 diffusion from speckles to the nucleoplasm brought on by regiospecific decreases in RS domain phosphorylation. Overall, these findings establish a molecular and biological connection between PP1-targeted amino acids in an RRM with the phosphorylation state and mRNA-processing function of an SR protein.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.004587