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.DOI: http://dx.doi.org/10.7554/eLife.02674.001.
Highlights
Human metapneumovirus (HMPV) is a negative-strand, non-segmented ssRNA virus of the Paramyxoviridae family and a major cause of acute respiratory tract infections in children, elderly and immunocompromised populations worldwide (van den Hoogen et al, 2002; van den Hoogen et al, 2003)
HMPV M2-1 forms a tetramer with an open and a closed conformation
M2-1 crystallized in space group P21 and its structure was solved at 2.5 Å resolution, by multiwavelength anomalous dispersion (MAD) using zinc anomalous scattering (Table 1)
Summary
Human metapneumovirus (HMPV) is a negative-strand, non-segmented ssRNA virus of the Paramyxoviridae family and a major cause of acute respiratory tract infections in children, elderly and immunocompromised populations worldwide (van den Hoogen et al, 2002; van den Hoogen et al, 2003). HMPV and the closely-related respiratory syncytial virus (RSV) constitute respectively the Metapneumovirus and Pneumovirus genera of the Pneumivirinae subfamily. These viruses share conserved replication strategies and similar genome organizations with other members of the Mononegavirales order, which includes numerous important human pathogens such as measles, rabies, and Ebola virus. The genomic RNA is encapsidated by the N protein, which acts as a template for the L protein that is responsible for both replication and transcription. The replicase is highly processive, and generates a complete, encapsidated positive-sense antigenome, which is in turn used as a template for the synthesis of genomic RNA. The transcriptase produces capped and polyadenylated monocistronic mRNAs using a sequential stop and restart mechanism in which the polymerase responds to cis-acting signals located in intergenic regions (Sutherland et al, 2001)
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