Conformational plasticity of the VEEV macro domain is important for binding of ADP-ribose.
Abstract: Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus which can be involved in several central nervous system disorders such as encephalitis and meningitis. The VEEV genome codes for 4 non-structural proteins (nsP), of which nsP3 contains a Macro domain. Macro domains (MD) can be found as stand-alone proteins or embedded within larger proteins in viruses, bacteria and eukaryotes. Their most common feature is the binding of ADP-ribose (ADPr), while several macro domains act as ribosylation writers, erasers or readers. Alphavirus MD erase ribosylation but their precise contribution in viral replication is still under investigation. NMR-driven titration experiments of ADPr in solution with the VEEV macro domain (in apo- and complex state) show that it adopts a suitable conformation for ADPr binding. Specific experiments indicate that the flexibility of the loops β5-α3 and α3-β6 is critical for formation of the complex and assists a wrapping mechanism for ADPr binding. Furthermore, along with this sequence of events, the VEEV MD undergoes a conformational exchange process between the apo state and a low-populated "dark" conformational state.
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Publication Date: 2019-02-27 PubMed ID: 30825649PubMed Central: PMC7111667DOI: 10.1016/j.jsb.2019.02.008Google Scholar: Lookup
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Summary
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The research paper discusses how the macro domain of the Venezuelan equine encephalitis virus (VEEV) easily changes shape (shows conformational plasticity) which helps it bind with the ADP-ribose, playing a critical role in viral replication.
The Venezuelan equine encephalitis virus (VEEV)
- The VEEV is an alphavirus that can cause a number of central nervous system disorders including encephalitis and meningitis.
- The VEEV genome codes for 4 non-structural proteins (nsP), out of which the nsP3 protein contains a macro domain.
Macro Domains (MD)
- Macro domains can be found as standalone proteins or as part of larger proteins in viruses, bacteria, and eukaryotes.
- The major feature of these macro domains is their ability to bind to ADP-ribose (ADPr), while many macro domains act as ribosylation writers, erasers or readers.
- Alphavirus MDs, such as the one in VEEV, are known to erase ribosylation, however, the exact role of this activity in the viral replication process requires further exploration.
Role of VEEV Macro Domain
- NMR-driven titration experiments were performed with ADPr in solution along with the VEEV macro domain (both in its free state (apo state) and in a complex state).
- Results from the experiment showed that the VEEV macro domain adopts a conformation favorable for ADPr binding.
- Further specificity tests have described the importance of the flexibility of loops β5-α3 and α3-β6 for the formation of a complex, facilitating a wrapping mechanism for ADPr binding.
Conformational Exchange Process of VEEV MD
- Alongside the chain of events described above, the VEEV macro domain was found to display a process of conformational exchange.
- It oscillated between its free state and a low-populated “dark” conformation state, both these observations were possible due to the use of NMR-driven titration experiments, hinting towards a potential strategy for viral replication.
Cite This Article
APA
Makrynitsa GI, Ntonti D, Marousis KD, Birkou M, Matsoukas MT, Asami S, Bentrop D, Papageorgiou N, Canard B, Coutard B, Spyroulias GA.
(2019).
Conformational plasticity of the VEEV macro domain is important for binding of ADP-ribose.
J Struct Biol, 206(1), 119-127.
https://doi.org/10.1016/j.jsb.2019.02.008 Publication
Researcher Affiliations
- Department of Pharmacy, University of Patras, GR-26504, Greece.
- Department of Pharmacy, University of Patras, GR-26504, Greece.
- Department of Pharmacy, University of Patras, GR-26504, Greece.
- Department of Pharmacy, University of Patras, GR-26504, Greece.
- Department of Pharmacy, University of Patras, GR-26504, Greece.
- Munich Center for Integrated Protein Science (CIPS-M) at Department Chemie, Technische Universität München (TUM), Lichtenbergstr. 4, 85747 Garching, Germany.
- Institute of Physiology II, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany.
- Aix Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
- Aix Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
- UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection, Marseille, France. Electronic address: Bruno.coutard@univ-amu.fr.
- Department of Pharmacy, University of Patras, GR-26504, Greece. Electronic address: G.A.Spyroulias@upatras.gr.
MeSH Terms
- Adenosine Diphosphate Ribose / chemistry
- Adenosine Diphosphate Ribose / metabolism
- Animals
- Encephalitis Virus, Venezuelan Equine / genetics
- Encephalitis Virus, Venezuelan Equine / metabolism
- Horses
- Humans
- Magnetic Resonance Spectroscopy
- Molecular Conformation
- Molecular Dynamics Simulation
- Protein Binding
- Protein Domains
- Viral Nonstructural Proteins / chemistry
- Viral Nonstructural Proteins / genetics
- Viral Nonstructural Proteins / metabolism
- Virus Replication
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