NMR study of non-structural proteins–part III: 1H, 13C, 15N backbone and side-chain resonance assignment of macro domain from Chikungunya virus (CHIKV)

Lykouras, Michail; Tsika, Aikaterini C.; Lichière, Julie; Papageorgiou, Nicolas; Coutard, Bruno; Bentrop, Detlef; Spyroulias, Georgios A.

doi:10.1007/s12104-017-9775-2

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…4 ). The order of the secondary structure segments corresponds almost exactly to that of the other viral MDs (Melekis et al 2015 ; Makrynitsa et al 2015 ; Lykouras et al 2018 ). Similarly free MERS–CoV MD protein (172 a.a.) has α/β/α sandwich-like fold which compares almost exactly with other SARS-CoV MD (Fig.…”

Section: Methods and Experimentssupporting

confidence: 57%

NMR study of macro domains (MDs) from betacoronavirus: backbone resonance assignments of SARS–CoV and MERS–CoV MDs in the free and the ADPr-bound state

et al. 2021

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Section: Methods and Experimentssupporting

confidence: 57%

NMR study of macro domains (MDs) from betacoronavirus: backbone resonance assignments of SARS–CoV and MERS–CoV MDs in the free and the ADPr-bound state

et al. 2021

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“…The N-terminal macro domain, first described as X-domain [ 75 ], is conserved among alphaviruses and homologous domains can also be found in proteins of other positive-strand RNA viruses (including rubella virus, some coronaviruses and hepatitis E virus), as well as some bacterial and cellular proteins [ 76 , 77 ]. Solution NMR spectroscopy of the CHIKV macro domain revealed a mixed α/β/α topology with 4 α-helices and 6 β-strands [ 78 ]. This is in agreement with the NMR structures obtained for the macro domains of MAYV [ 79 ] and VEEV [ 80 ] and the crystal structures of the CHIKV & VEEV macro domains [ 81 ].…”

Section: The Macro Domainmentioning

confidence: 99%

The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last

Götte

Liu

McInerney

2018

Viruses

104

162

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Alphaviruses encode 4 non-structural proteins (nsPs), most of which have well-understood functions in capping and membrane association (nsP1), polyprotein processing and RNA helicase activity (nsP2) and as RNA-dependent RNA polymerase (nsP4). The function of nsP3 has been more difficult to pin down and it has long been referred to as the more enigmatic of the nsPs. The protein comprises three domains, an N-terminal macro domain, a central zinc-binding domain and a C-terminal hypervariable domain (HVD). In this article, we review old and new literature about the functions of the three domains. Much progress in recent years has contributed to a picture of nsP3, particularly through its HVD as a hub for interactions with host cell molecules, with multiple effects on the biology of the host cell at early points in infection. These and many future discoveries will provide targets for anti-viral therapies as well as strategies for modification of vectors for vaccine and oncolytic interventions.

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“…The hypervariable domain interacts with multiple cellular proteins important for virus replication (13)(14)(15)(16)(17)(18), and the zinc-binding domain has a role in the synthesis of viral RNA (19)(20)(21)(22). The highly conserved MD consists of a central beta sheet surrounded by four to six helices, a protein fold that exists in all kingdoms of life, including a few families of plus-strand RNA viruses (23)(24)(25)(26)(27). MDs bind ADP-ribose (ADPr) on proteins posttranslationally modified by either monomers or polymers of ADPr, a modification known as ADP-ribosylation.…”

mentioning

confidence: 99%

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Abraham

McPherson

Dasovich

et al. 2020

mBio

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Macrodomain (MD), a highly conserved protein fold present in a subset of plus-strand RNA viruses, binds to and hydrolyzes ADP-ribose (ADPr) from ADPribosylated proteins. ADPr-binding by the alphavirus nonstructural protein 3 (nsP3) MD is necessary for the initiation of virus replication in neural cells, whereas hydrolase activity facilitates replication complex amplification. To determine the importance of these activities for pathogenesis of alphavirus encephalomyelitis, mutations were introduced into the nsP3 MD of Sindbis virus (SINV), and the effects on ADPr binding and hydrolase activities, virus replication, immune responses, and disease were assessed. Elimination of ADPr-binding and hydrolase activities (G32E) severely impaired in vitro replication of SINV in neural cells and in vivo replication in the central nervous systems of 2-week-old mice with reversion to wild type (WT) (G) or selection of a less compromising change (S) during replication. SINVs with decreased binding and hydrolase activities (G32S and G32A) or with hydrolase deficiency combined with better ADPr-binding (Y114A) were less virulent than WT virus. Compared to the WT, the G32S virus replicated less well in both the brain and spinal cord, induced similar innate responses, and caused less severe disease with full recovery of survivors, whereas the Y114A virus replicated well, induced higher expression of interferon-stimulated and NF-B-induced genes, and was cleared more slowly from the spinal cord with persistent paralysis in survivors. Therefore, MD function was important for neural cell replication both in vitro and in vivo and determined the outcome from alphavirus encephalomyelitis in mice. IMPORTANCE Viral encephalomyelitis is an important cause of long-term disability, as well as acute fatal disease. Identifying viral determinants of outcome helps in assessing disease severity and developing new treatments. Mosquito-borne alphaviruses infect neurons and cause fatal disease in mice. The highly conserved macrodomain of nonstructural protein 3 binds and can remove ADP-ribose (ADPr) from ADPribosylated proteins. To determine the importance of these functions for virulence, recombinant mutant viruses were produced. If macrodomain mutations eliminated ADPr-binding or hydrolase activity, viruses did not grow. If the binding and hydrolase activities were impaired, the viruses grew less well than the wild-type virus, induced similar innate responses, and caused less severe disease, and most of the infected mice recovered. If binding was improved, but hydrolase activity was decreased, the virus replicated well and induced greater innate responses than did the WT, but clearance from the nervous system was impaired, and mice remained paralyzed. Therefore, macrodomain function determined the outcome of alphavirus encephalomyelitis. Citation Abraham R, McPherson RL, Dasovich M, Badiee M, Leung AKL, Griffin DE. 2020. Both ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain affect neurovirulence in mice. mBio 11:e03253-1...

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NMR study of non-structural proteins–part III: 1H, 13C, 15N backbone and side-chain resonance assignment of macro domain from Chikungunya virus (CHIKV)

Cited by 8 publications

References 17 publications

NMR study of macro domains (MDs) from betacoronavirus: backbone resonance assignments of SARS–CoV and MERS–CoV MDs in the free and the ADPr-bound state

NMR study of macro domains (MDs) from betacoronavirus: backbone resonance assignments of SARS–CoV and MERS–CoV MDs in the free and the ADPr-bound state

The Enigmatic Alphavirus Non-Structural Protein 3 (nsP3) Revealing Its Secrets at Last

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

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