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Molecular mechanism of SR protein kinase 1 inhibition by the herpes virus protein ICP27

DOI: 10.1128/mBio.02551-19 DOI Help

Authors: Richard B. Tunnicliffe (The University of Manchester) , William K. Hu (University of California, Irvine) , Michele Y. Wu (University of California, Irvine) , Colin Levy (The University of Manchester) , A. Paul Mould (The University of Manchester) , Edward A. Mckenzie (The University of Manchester) , Rozanne M. Sandri-goldin (University of California, Irvine) , Alexander P. Golovanov (The University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Mbio , VOL 10

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 12788

Open Access Open Access

Abstract: Serine-arginine (SR) protein kinase 1 (SRPK1) catalyzes the phosphorylation of SR proteins, which are a conserved family of splicing factors that contain a domain rich in arginine and serine repeats. SR proteins play important roles in constitutive pre-mRNA splicing and are also important regulators of alternative splicing. During herpes simplex virus infection, SRPK1 is inactivated and its cellular distribution is markedly altered by interaction with the viral protein ICP27, resulting in hypophosphorylation of SR proteins. Mutational analysis previously showed that the RGG box motif of ICP27 is required for interaction with SRPK1; however, the mechanism for the inhibition and the exact role of the RGG box was unknown. Here, we used solution nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC) to demonstrate that the isolated peptide comprising the RGG box of ICP27 binds to SRPK1 with high affinity, competing with a native substrate, the SR repeat region of SR protein SRSF1. We determined the crystal structure of the complex between SRPK1 and an RGG box peptide, which revealed that the viral peptide binds to the substrate docking groove, mimicking the interactions of SR repeats. Site-directed mutagenesis within the RGG box further confirmed the importance of selected arginine residues for interaction, relocalization, and inhibition of SRPK1 in vivo. Together these data reveal the molecular mechanism of the competitive inhibition of cellular SRPK1 by viral ICP27, which modulates SRPK1 activity

Journal Keywords: phosphorylation; splicing; herpes simplex virus; structure; phosphorylation; SR protein kinase

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)


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