Intrinsically disordered protein domains in flavivirus infection

Martins, Ivo C.; Santos, Nuno C.

doi:10.1016/j.abb.2020.108298

Cited by 10 publications

(10 citation statements)

References 122 publications

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“…In addition, the analysis of the NSs amino acid sequences with the PONDR software (Figure 4c) showed that the NSs of low and non-pathogenic viruses, TULV, and PHV displayed a higher level of disordering than PUUV-NSs protein in the N-ter region containing the NoLS. Of note, protein disordering is a feature that is usually associated to a high capacity of interaction [41,42]. The NoLS corresponding regions of TULV and PHV possess a polar motif positively charged, KRR 16-18 and NGR 16-18 respectively, while, in the PUUV NSs protein, different polar residues with positive and negative charges were found in the corresponding region, REQ [16][17][18] , as shown by alignment of the NSs protein sequences (Figure 4d).…”

Section: Nss Sequence Analysismentioning

confidence: 99%

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling

Gallo

Caignard

Badonnel

et al. 2021

Viruses

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Rodent-borne orthohantaviruses are asymptomatic in their natural reservoir, but they can cause severe diseases in humans. Although an exacerbated immune response relates to hantaviral pathologies, orthohantaviruses have to antagonize the antiviral interferon (IFN) response to successfully propagate in infected cells. We studied interactions of structural and nonstructural (NSs) proteins of pathogenic Puumala (PUUV), low-pathogenic Tula (TULV), and non-pathogenic Prospect Hill (PHV) viruses, with human type I and III IFN (IFN-I and IFN-III) pathways. The NSs proteins of all three viruses inhibited the RIG-I-activated IFNβ promoter, while only the glycoprotein precursor (GPC) of PUUV, or its cleavage product Gn/Gc, and the nucleocapsid (N) of TULV inhibited it. Moreover, the GPC of both PUUV and TULV antagonized the promoter of IFN-stimulated responsive elements (ISRE). Different viral proteins could thus contribute to inhibition of IFNβ response in a viral context. While PUUV and TULV strains replicated similarly, whether expressing entire or truncated NSs proteins, only PUUV encoding a wild type NSs protein led to late IFN expression and activation of IFN-stimulated genes (ISG). This, together with the identification of particular domains of NSs proteins and different biological processes that are associated with cellular proteins in complex with NSs proteins, suggested that the activation of IFN-I is probably not the only antiviral pathway to be counteracted by orthohantaviruses and that NSs proteins could have multiple inhibitory functions.

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Section: Nss Sequence Analysismentioning

confidence: 99%

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling

Gallo

Caignard

Badonnel

et al. 2021

Viruses

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“…The flaviviruses polyprotein is very rich in disordered regions [77,78], with the C protein being an excellent tracker of Flavivirus spp. phylogeny [76] (Figure 3).…”

Section: The Flavivirus Proteomementioning

confidence: 99%

“…The C protein is thus a good indicator of viral evolution. These disordered regions enable flavivirus small proteomes to have a large interactome, enabling multiple functions [78,79]. Flaviviruses are a paradigm for the role of IDPs in increasing viral functions.…”

Section: The Flavivirus Proteomementioning

confidence: 99%

“…There is an asymmetric charge distribution, with most positive charges of DENV C concentrated in one side of the dimer, formed by the α4 helices of each monomer (α4-α4'), while the opposite side has a higher density of non-polar residues. This is intimately related with the Flavivirus C proteins' function(s), with the α4-α4' region being likely responsible for interaction with the viral RNA, assisting in the viral genome packaging, whereas the α2-α2' region interacts with host lipid systems (Figure 2b) [69,76,78,81,84,85].…”

Section: The Flavivirus C Proteinsmentioning

confidence: 99%

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Dengue and Zika Viruses: Epidemiological History, Potential Therapies, and Promising Vaccines

2020

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Dengue virus (DENV), which can lead to fatal hemorrhagic fever, affects 390 million people worldwide. The closely related Zika virus (ZIKV) causes microcephaly in newborns and Guillain-Barré syndrome in adults. Both viruses are mostly transmitted by Aedes albopictus and Aedes aegypti mosquitoes, which, due to globalization of trade and travel alongside climate change, are spreading worldwide, paving the way to DENV and ZIKV transmission and the occurrence of new epidemics. Local outbreaks have already occurred in temperate climates, even in Europe. As there are no specific treatments, these viruses are an international public health concern. Here, we analyze and discuss DENV and ZIKV outbreaks history, clinical and pathogenesis features, and modes of transmission, supplementing with information on advances on potential therapies and restraining measures. Taking advantage of the knowledge of the structure and biological function of the capsid (C) protein, a relatively conserved protein among flaviviruses, within a genus that includes DENV and ZIKV, we designed and patented a new drug lead, pep14-23 (WO2008/028939A1). It was demonstrated that it inhibits the interaction of DENV C protein with the host lipid system, a process essential for viral replication. Such an approach can be used to develop new therapies for related viruses, such as ZIKV.

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“…The flavivirus genome is well adapted to function under disparate environmental stressors, even when changes in sequence compromise replication efficiency. Such an adaptive mechanism may also explain the prevalence of disordered regions throughout the flavivirus proteome [34]. These disordered regions increase the functional diversity of a finite viral proteome by conferring a greater potential for viral-host protein interactions [35].…”

Section: Structure Duplication Within the 3 Utr And Flavivirus Host Switchingmentioning

confidence: 99%

The Pseudo-Circular Genomes of Flaviviruses: Structures, Mechanisms, and Functions of Circularization

Falco

Silva

Santos

et al. 2021

Cells

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The circularization of viral genomes fulfills various functions, from evading host defense mechanisms to promoting specific replication and translation patterns supporting viral proliferation. Here, we describe the genomic structures and associated host factors important for flaviviruses genome circularization and summarize their functional roles. Flaviviruses are relatively small, single-stranded, positive-sense RNA viruses with genomes of approximately 11 kb in length. These genomes contain motifs at their 5′ and 3′ ends, as well as in other regions, that are involved in circularization. These motifs are highly conserved throughout the Flavivirus genus and occur both in mature virions and within infected cells. We provide an overview of these sequence motifs and RNA structures involved in circularization, describe their linear and circularized structures, and discuss the proteins that interact with these circular structures and that promote and regulate their formation, aiming to clarify the key features of genome circularization and understand how these affect the flaviviruses life cycle.

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Intrinsically disordered protein domains in flavivirus infection

Cited by 10 publications

References 122 publications

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling

Dengue and Zika Viruses: Epidemiological History, Potential Therapies, and Promising Vaccines

The Pseudo-Circular Genomes of Flaviviruses: Structures, Mechanisms, and Functions of Circularization

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