Drastic changes in conformational dynamics of the antiterminator M2-1 regulate transcription efficiency in Pneumovirinae

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Abstract

The M2-1 protein of human metapneumovirus (HMPV) is a zinc-binding transcription antiterminator which is highly conserved among pneumoviruses. We report the structure of tetrameric HMPV M2-1. Each protomer features a N-terminal zinc finger domain and an α-helical tetramerization motif forming a rigid unit, followed by a flexible linker and an α-helical core domain. The tetramer is asymmetric, three of the protomers exhibiting a closed conformation, and one an open conformation. Molecular dynamics simulations and SAXS demonstrate a dynamic equilibrium between open and closed conformations in solution. Structures of adenosine monophosphate- and DNA- bound M2-1 establish the role of the zinc finger domain in base-specific recognition of RNA. Binding to 'gene end' RNA sequences stabilized the closed conformation of M2-1 leading to a drastic shift in the conformational landscape of M2-1. We propose a model for recognition of gene end signals and discuss the implications of these findings for transcriptional regulation in pneumoviruses.

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Cedric Leyrat

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Max Renner

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Karl Harlos

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Juha T Huiskonen

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Jonathan M Grimes

Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

For correspondence
jonathan@strubi.ox.ac.uk

Competing interests
The authors declare that no competing interests exist.

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