An ultraweak interaction in the intrinsically disordered replication machinery is essential for measles virus function

Science Advances
Sigrid MillesMartin Blackledge

Abstract

Measles virus genome encapsidation is essential for viral replication and is controlled by the intrinsically disordered phosphoprotein (P) maintaining the nucleoprotein in a monomeric form (N) before nucleocapsid assembly. All paramyxoviruses harbor highly disordered amino-terminal domains (PNTD) that are hundreds of amino acids in length and whose function remains unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we describe the structure and dynamics of the 90-kDa N0PNTD complex, comprising 450 disordered amino acids, at atomic resolution. NMR relaxation dispersion reveals the existence of an ultraweak N-interaction motif, hidden within the highly disordered PNTD, that allows PNTD to rapidly associate and dissociate from a specific site on N while tightly bound at the amino terminus, thereby hindering access to the surface of N. Mutation of this linear motif quenches the long-range dynamic coupling between the two interaction sites and completely abolishes viral transcription/replication in cell-based minigenome assays comprising integral viral replication machinery. This description transforms our understanding of intrinsic conformational disorder in paramyxoviral replication. The essential mechanism appears to b...Continue Reading

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Citations

Feb 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Ambroise DesfossesMartin Blackledge
May 16, 2019·Science Advances·Louis-Marie BloyetDenis Gerlier
Jun 14, 2019·Journal of Virology·Elizabeth B Wignall-FlemingRichard E Randall
Jul 2, 2019·Science Advances·Nicola SalviMartin Blackledge
Sep 10, 2019·Frontiers in Microbiology·Serafima GusevaRob W H Ruigrok
Jul 23, 2020·Nature Communications·Aldo R Camacho-ZarcoMartin Blackledge
Nov 22, 2019·Journal of Virology·Christian K PfallerRoberto Cattaneo
Jul 22, 2019·Archives of Biochemistry and Biophysics·Angelo TotoStefano Gianni
Dec 14, 2019·Current Opinion in Structural Biology·T Reid Alderson, Lewis E Kay
Apr 30, 2020·Biophysical Journal·Malene Ringkjøbing JensenMarc Jamin
Jun 19, 2021·Virus Evolution·Jordan DouglasRichard L Kingston
Aug 22, 2021·Journal of Molecular Biology·Kiersten M Ruff, Rohit V Pappu
Sep 16, 2021·The EMBO Journal·Florian GeigerAlexander Borodavka
Nov 25, 2021·Journal of the American Chemical Society·Samuel Naudi-FabraSigrid Milles

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Methods Mentioned

BETA
nuclear
x-ray scattering
NMR
size exclusion chromatography

Software Mentioned

MUSCLE
flexible
meccano
WebLogo
ASTEROIDS
PSIPRED
NMRPipe
CRYSOL
SPARTA
MARS

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