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Structural Analysis of the Menangle Virus P Protein Reveals a Soft Boundary between Ordered and Disordered Regions
Melissa N Webby1,2, Nicole Herr1, Esther M M Bulloch1
1School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand.
Abstract:
The paramyxoviral phosphoprotein (P protein) is the non-catalytic subunit of the viral RNA polymerase, and coordinates many of the molecular interactions required for RNA synthesis. All paramyxoviral P proteins oligomerize via a centrally located coiled-coil that is connected to a downstream binding domain by a dynamic linker. The C-terminal region of the P protein coordinates interactions between the catalytic subunit of the polymerase, and the viral nucleocapsid housing the genomic RNA. The inherent flexibility of the linker is believed to facilitate polymerase translocation. Here we report biophysical and structural characterization of the C-terminal region of the P protein from Menangle virus (MenV), a bat-borne paramyxovirus with zoonotic potential. The MenV P protein is tetrameric but can dissociate into dimers at sub-micromolar protein concentrations. The linker is globally disordered and can be modeled effectively as a worm-like chain. However, NMR analysis suggests very weak local preferences for alpha-helical and extended beta conformation exist within the linker. At the interface between the disordered linker and the structured C-terminal binding domain, a gradual disorder-to-order transition occurs, with X-ray crystallographic analysis revealing a dynamic interfacial structure that wraps the surface of the binding domain.
Insights
The Menangle virus phosphoprotein (P protein) has a flexible linker crucial for RNA synthesis. Biophysical studies reveal its C-terminal region
Area of Science:
- Virology
- Structural Biology
- Biochemistry
Background:
- Paramyxoviral phosphoprotein (P protein) is essential for viral RNA synthesis.
- P protein structure includes a coiled-coil oligomerization domain, a dynamic linker, and a C-terminal binding domain.
- The linker's flexibility is hypothesized to aid viral polymerase translocation.
Purpose of the Study:
- To characterize the C-terminal region of the Menangle virus (MenV) phosphoprotein.
- To investigate the structural and biophysical properties of the MenV P protein's flexible linker and binding domain.
- To understand the MenV P protein's role in viral RNA synthesis and its potential zoonotic implications.
Main Methods:
- X-ray crystallography
- Nuclear Magnetic Resonance (NMR) spectroscopy
- Biophysical characterization (e.g., protein concentration studies)
Main Results:
- Menangle virus P protein forms tetramers that can dissociate into dimers.
- The linker region is globally disordered, behaving as a worm-like chain with minor local conformational preferences.
- A disorder-to-order transition occurs at the linker-binding domain interface, forming a dynamic structure.
Conclusions:
- The Menangle virus P protein exhibits unique structural dynamics in its C-terminal region.
- The disordered linker and dynamic interface likely play a role in viral RNA polymerase function.
- Understanding MenV P protein structure provides insights into paramyxovirus replication and zoonotic potential.
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