Bipartite interface of the measles virus phosphoprotein X domain with the large polymerase protein regulates viral polymerase dynamics

PLoS Pathogens
Venice Du PontRichard K Plemper

Abstract

Measles virus (MeV) is a highly contagious, re-emerging, major human pathogen. Replication requires a viral RNA-dependent RNA polymerase (RdRP) consisting of the large (L) polymerase protein complexed with the homo-tetrameric phosphoprotein (P). In addition, P mediates interaction with the nucleoprotein (N)-encapsidated viral RNA genome. The nature of the P:L interface and RdRP negotiation of the ribonucleoprotein template are poorly understood. Based on biochemical interface mapping, swapping of the central P tetramerization domain (OD) for yeast GCN4, and functional assays, we demonstrate that the MeV P-to-L interface is bipartite, comprising a coiled-coil microdomain proximal to the OD and an unoccupied face of the triangular prism-shaped C-terminal P X-domain (P-XD), which is distinct from the known P-XD face that binds N-tail. Mixed null-mutant P tetramers regained L-binding competence in a ratio-dependent manner and fully reclaimed bioactivity in minireplicon assays and recombinant MeV, demonstrating that the individual L-binding interface elements are physically and mechanistically distinct. P-XD binding competence to L and N was likewise trans-complementable, which, combined with mathematical modeling, enabled the mecha...Continue Reading

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Citations

Jan 18, 2020·The Journal of Biological Chemistry·Chanakha K NavaratnarajahRoberto Cattaneo
Feb 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ryan AbdellaYuan He
Nov 22, 2019·Journal of Virology·Christian K PfallerRoberto Cattaneo
Mar 7, 2021·Viruses·Temitope Akhigbe EtiborMaria João Amorim
Jun 19, 2021·Virus Evolution·Jordan DouglasRichard L Kingston

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Methods Mentioned

BETA
co-IP
co-immunoprecipitation
co-IPs
dissection
PCR
transfection
immunoprecipitations
scraping

Software Mentioned

Clustal Omega
Gen5
Prism
NEBuilder
GeneWiz
Isqcurvefit Toolbox
MoRE
Graph Pad
MATLAB

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