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

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 ?-helical tetramerization motif forming a rigid unit, followed by a flexible linker and an ?-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.

SUBMITTER: Leyrat C

PROVIDER: S-EPMC4051120 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Leyrat Cedric C Renner Max M Harlos Karl K Huiskonen Juha T JT Grimes Jonathan M JM

eLife 20140519

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 dynamic ...[more]

PMID: 24842877

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Project description:Changes in protein conformation play key roles in facilitating various biochemical processes, ranging from signaling and phosphorylation to transport and catalysis. While various factors that drive these motions such as environmental changes and binding of small molecules are well understood, specific causative effects on the structural features of the protein due to these conformational changes have not been studied on a large scale. Here, we study protein conformational changes in relation to two key structural metrics: packing efficiency and disorder. Packing has been shown to be crucial for protein stability and function by many protein design and engineering studies. We study changes in packing efficiency during conformational changes, thus extending the analysis from a static context to a dynamic perspective and report some interesting observations. First, we study various proteins that adopt alternate conformations and find that tendencies to show motion and change in packing efficiency are correlated: residues that change their packing efficiency show larger motions. Second, our results suggest that residues that show higher changes in packing during motion are located on the changing interfaces which are formed during these conformational changes. These changing interfaces are slightly different from shear or static interfaces that have been analyzed in previous studies. Third, analysis of packing efficiency changes in the context of secondary structure shows that, as expected, residues buried in helices show the least change in packing efficiency, whereas those embedded in bends are most likely to change packing. Finally, by relating protein disorder to motions, we show that marginally disordered residues which are ordered enough to be crystallized but have sequence patterns indicative of disorder show higher dislocation and a higher change in packing than ordered ones and are located mostly on the changing interfaces. Overall, our results demonstrate that between the two conformations, the cores of the proteins remain mostly intact, whereas the interfaces display the most elasticity, both in terms of disorder and change in packing efficiency. By doing a variety of tests, we also show that our observations are robust to the solvation state of the proteins.

Dataset Information

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

Publications

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

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