Maintaining pH-dependent conformational flexibility of M1 is critical for efficient influenza A virus replication

Chiang, Meng-Jung; Musayev, F.N.; Košíková, Martina; Lin, Zhengshi; Gao, Yamei; Mosier, Philip D.; Althufairi, Bashayer; Ye, Zhiping; Zhou, Qibing; Desai, Umesh R.; Xie, Hang

doi:10.1038/emi.2017.96

Cited by 10 publications

(9 citation statements)

References 41 publications

(112 reference statements)

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“…The structure of the NTD is essentially identical to that of N-terminal fragment structures previously determined by X-ray crystallography (1aa7 10 ,1ea3 11 , 5v6g 26 ) with the exception of the helix4/5 loop which adopts a different conformation (Extended data Fig. 6).…”

Section: Influenza a Virus Causes Millions Of Severe Illnesses Duringsupporting

confidence: 71%

The native structure of the full-length, assembled influenza A virus matrix protein, M1

Peukes

Xiong

Erlendsson

et al. 2020

Preprint

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Influenza A virus causes millions of severe illnesses during annual epidemics. The most abundant protein in influenza virions is the matrix protein M1 that mediates virus assembly by forming an endoskeleton beneath the virus membrane. The structure of full-length M1, and how it oligomerizes to mediate assembly of virions, is unknown. Here we have determined the complete structure of assembled M1 within intact virus particles, as well as the structure of M1 oligomers reconstituted in vitro. We found that the C-terminal domain of M1 is disordered in solution, but can fold and bind in trans to the N-terminal domain of another M1 monomer, thus polymerising M1 into linear strands which coat the interior surface of the assembling virion membrane. In the M1 polymer, five histidine residues, contributed by three different M1 monomers, form a cluster that can serve as the pH-sensitive disassembly switch after entry into a target cell. These structures therefore provide mechanisms for influenza virus assembly and disassembly.

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Section: Influenza a Virus Causes Millions Of Severe Illnesses Duringsupporting

confidence: 71%

The native structure of the full-length, assembled influenza A virus matrix protein, M1

Peukes

Xiong

Erlendsson

et al. 2020

Preprint

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“…To investigate the molecular interactions of M1 within the multilayered oligomers, we analyzed the effect of engineered point mutations on assembly, guided by the available crystal structures of NTD M1 ( S1 Fig ) [ 2 , 14 , 15 , 21 ]. Mutation of V97 to a lysine, predicted to disrupt hydrophobic interactions at either of the C2-symmetry and lateral interfaces observed by crystallography, led to the formation of single-layered oligomers ( Fig 3A ).…”

Section: Resultsmentioning

confidence: 99%

Full-length three-dimensional structure of the influenza A virus M1 protein and its organization into a matrix layer

Selzer

Pintilie

et al. 2020

PLoS Biol

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Matrix proteins are encoded by many enveloped viruses, including influenza viruses, herpes viruses, and coronaviruses. Underneath the viral envelope of influenza virus, matrix protein 1 (M1) forms an oligomeric layer critical for particle stability and pH-dependent RNA genome release. However, high-resolution structures of full-length monomeric M1 and the matrix layer have not been available, impeding antiviral targeting and understanding of the pHdependent transitions involved in cell entry. Here, purification and extensive mutagenesis revealed protein-protein interfaces required for the formation of multilayered helical M1 oligomers similar to those observed in virions exposed to the low pH of cell entry. However, single-layered helical oligomers with biochemical and ultrastructural similarity to those found in infectious virions before cell entry were observed upon mutation of a single amino acid. The highly ordered structure of the single-layered oligomers and their likeness to the matrix layer of intact virions prompted structural analysis by cryo-electron microscopy (cryo-EM). The resulting 3.4-Å-resolution structure revealed the molecular details of M1 folding and its organization within the single-shelled matrix. The solution of the full-length M1 structure, the identification of critical assembly interfaces, and the development of M1 assembly assays with purified proteins are crucial advances for antiviral targeting of influenza viruses.

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“…All viruses including human H5N1 A/Vietnam/1203/2004 (VN/1203) vaccine reassortant bearing a monobasic cleavage site in HA [29], H1N1 A/Michigan/45/2015 and H3N2 A/Hong Kong/4801/2014 were propagated in 9–11-day-old embryonated eggs at 33°C. Infectious viral particles were determined by a plaque assay [29,30].…”

Section: Methodsmentioning

confidence: 99%

Pregnancy level of estradiol attenuated virus-specific humoral immune response in H5N1-infected female mice despite inducing anti-inflammatory protection

Finch

Zhang

Košíková

et al. 2019

Emerging Microbes & Infections

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Estradiol, a major female steroid produced during pregnancy, has been reported to protect ovariectomized animals against H1N1 influenza infections via its anti-inflammatory effects. However, it remains unclear why pregnant women with high gestational estradiol levels are highly susceptible to influenza infections. This study was aimed to investigate the effects of pregnancy level of estradiol on female immunity against H5N1 infection in Balb/c mice. A sex-dependent susceptibility to H5N1 infection (higher morbidity and higher mortality) was observed in both pregnant and non-pregnant female mice as compared to male mice. Subcutaneous implantation of estradiol pellets increased serum estradiol concentrations of non-pregnant female mice to the pregnancy level. These mice were protected from H5N1 infection through downregulation of pulmonary pro-inflammatory cytokines. However, the production of virus-specific antibodies after infection was significantly delayed in estradiol-implanted mice when compared to placebos. Virus-specific IgG-secreting and IL-4-secreting cells were also reduced in estradiol-implanted mice. Similarly, lower antibody titers to seasonal vaccine antigens were found in pregnant women as compared to non-pregnant females without hormone usage. Our results indicate that estradiol levels equivalent to those found during pregnancy have divergent effects on female immunity against influenza, highlighting the importance of vaccination during pregnancy to prevent severe influenza infections.

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Maintaining pH-dependent conformational flexibility of M1 is critical for efficient influenza A virus replication

Cited by 10 publications

References 41 publications

The native structure of the full-length, assembled influenza A virus matrix protein, M1

The native structure of the full-length, assembled influenza A virus matrix protein, M1

Full-length three-dimensional structure of the influenza A virus M1 protein and its organization into a matrix layer

Pregnancy level of estradiol attenuated virus-specific humoral immune response in H5N1-infected female mice despite inducing anti-inflammatory protection

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