Amphipathic alpha-helices and putative cholesterol binding domains of the influenza virus matrix M1 protein are crucial for virion structure organisation

Tsfasman, Tatyana; Kost, V Yu; Markushin, S. G.; Lotte, V. D.; Коптяева, И Б; Bogacheva, E. N.; Baratova, Ludmila A.; Radyukhin, V. A.

doi:10.1016/j.virusres.2015.07.017

Cited by 16 publications

(14 citation statements)

References 12 publications

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“…The results support recent speculation (39) that M2 may not be the only factor required for influenza virus membrane scission, because the beads-on-string particles seen in viruses that do not encode M2 or encode mutations in the M2 membrane-proximal regions do not seem to contain a complete M1 layer (39). The M1 structure is composed of multiple amphipathic helices and has putative cholesterol binding domains, and M1 alone can induce membrane curvature (20,21,40,41). Future experiments assessing the contribution of M1 and M2 to membrane scission in virus-infected cells are needed.…”

Section: Discussionsupporting

confidence: 88%

“…M1 suppressor residues 93 and 94 and known residues that affect virus morphology (aa 92, 95, 101, and 102) are located in the amphipathic helix 6 (15). Residues 93 and 94 are located on the side that was suggested to interact with lipid raft membranes, and residues on the other side of the helix (R/K95, K98, and K102) have been shown to directly interact with vRNP (15,40). M1 suppressor residues 94 and 136, residues in helix 6, and almost all other known residues within the N-terminal and middle domains that affect virus morphology were proposed to be involved in M1-M1 interactions under certain conditions (22,23).…”

Section: Discussionmentioning

confidence: 99%

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Mutations in the Influenza A Virus M1 Protein Enhance Virus Budding To Complement Lethal Mutations in the M2 Cytoplasmic Tail

Liu

Grantham

Pekosz

2018

J Virol

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The influenza A virus M1 and M2 proteins play important roles in virus assembly and in the morphology of virus particles. Mutations in the distal cytoplasmic tail region of M2, and in particular a tyrosine-to-alanine mutation at residue 76 (Y76A), were essential for infectious virus production and filament formation while having limited effects on total virus particle budding. Using a novel selection method, mutations at seven different M1 amino acids (residue 73, 94, 135, 136, or 138 or a double mutation, 93/244) that are not found in circulating influenza virus strains or have not been previously identified to play a role in influenza A virus assembly were found to complement the lethal M2Y76A mutation. These M1 suppressor mutations restored infectious virus production in the presence of M2Y76A and mediated increased budding and filament formation even in the absence of M2. However, the efficiency of infectious virus replication was still dependent on the presence of the distal region of the M2 cytoplasmic tail. The data suggest that influenza A virus budding and genome incorporation can occur independently and provide further support for complementary roles of the M1 and M2 proteins in virus assembly. Influenza virus particle assembly involves the careful coordination of various viral and host factors to optimally produce infectious virus particles. We have previously identified a mutation at position 76 of the influenza A virus M2 protein that drastically reduces infectious virus production and filament formation with minimal effects on virus budding. In this work, we identified suppressor mutations in the M1 protein which complement this lethal M2 mutation by increasing the efficiency with which virus particles bud from infected cells and restoring filament formation at the infected-cell surface. M2 distal cytoplasmic domain sequences were still required for optimal infectivity. This indicates that M1 and M2 can functionally replace each other in some, but not all, aspects of virus particle assembly.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Mutations in the Influenza A Virus M1 Protein Enhance Virus Budding To Complement Lethal Mutations in the M2 Cytoplasmic Tail

Liu

Grantham

Pekosz

2018

J Virol

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“…In 16 authors analyze the X-ray crystal structures of N-terminal domain of M1 protein and hypothesize the insertion of this domain into the viral lipid membrane. This insertion may be possible, as it was shown later, due to the presence of amphipathic helices in the N-terminal domain structure 28 . The possibility hydrophobic forces being involved in the interactions of M1 with lipid membranes is also mentioned in 29 based on the emission spectrum of the fluorescent probe 12-(9-anthroyl)-stearic acid incorporated into viral particles with removed glycoprotein spikes.…”

Section: Introductionmentioning

confidence: 63%

Influenza virus Matrix Protein M1 preserves its conformation with pH, changing multimerization state at the priming stage due to electrostatics

Shtykova

Dadinova

Федорова

et al. 2017

Sci Rep

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Influenza A virus matrix protein M1 plays an essential role in the virus lifecycle, but its functional and structural properties are not entirely defined. Here we employed small-angle X-ray scattering, atomic force microscopy and zeta-potential measurements to characterize the overall structure and association behavior of the full-length M1 at different pH conditions. We demonstrate that the protein consists of a globular N-terminal domain and a flexible C-terminal extension. The globular N-terminal domain of M1 monomers appears preserved in the range of pH from 4.0 to 6.8, while the C-terminal domain remains flexible and the tendency to form multimers changes dramatically. We found that the protein multimerization process is reversible, whereby the binding between M1 molecules starts to break around pH 6. A predicted electrostatic model of M1 self-assembly at different pH revealed a good agreement with zeta-potential measurements, allowing one to assess the role of M1 domains in M1-M1 and M1-lipid interactions. Together with the protein sequence analysis, these results provide insights into the mechanism of M1 scaffold formation and the major role of the flexible and disordered C-terminal domain in this process.

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“…CRAC motifs are found in alpha-helices of matrix protein M1 of influenza A virus [105][106][107]. An important role of these CRAC motifs in the organization of the raft structure of the virion membrane was substantiated by using the method of directed point mutations in the CRAC-containing α-helices in the M1 protein [106,107].…”

Section: Cholesterol Recognition/interaction Amino Acid Consensus (Crmentioning

confidence: 99%

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

Dunina-Barkovskaya¹

2021

Management of Dyslipidemia

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Some interactions of enveloped viruses with the host cell membrane have a cholesterol-dependent component, which may account for clinical manifestations of the infectious disease and can be used for the development of antiviral drugs. These cholesterol-dependent interactions can be mediated by cholesterol-recognition amino-acid consensus (CRAC) motifs present in viral proteins. The S protein of the SARS-CoV and SARS-CoV2 coronaviruses contains CRAC motifs that can be involved in the process of virus entry into the cell. Besides, during viral envelope formation, CRAC motifs can be responsible for binding of cell membrane cholesterol, leading to depletion of cell membrane cholesterol and subsequent malfunctioning of cellular cholesterol-dependent proteins, destabilization and permeabilization of cell membranes and, ultimately, to the death of infected cells. Understanding the mechanisms of cholesterol-dependent virus–cell interactions and the role of CRAC-containing viral proteins in the pathogenesis of the disease can serve as the basis for the development of new drugs that prevent both coronavirus entry into the cell and the damage of the infected cell during the viral morphogenesis. The target for such drugs can be the S-protein/cholesterol interface. CRAC-containing peptides derived from viral proteins may be among these agents. These peptides can also be used as experimental tools to study cholesterol-dependent virus–cell interactions.

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Amphipathic alpha-helices and putative cholesterol binding domains of the influenza virus matrix M1 protein are crucial for virion structure organisation

Cited by 16 publications

References 12 publications

Mutations in the Influenza A Virus M1 Protein Enhance Virus Budding To Complement Lethal Mutations in the M2 Cytoplasmic Tail

Mutations in the Influenza A Virus M1 Protein Enhance Virus Budding To Complement Lethal Mutations in the M2 Cytoplasmic Tail

Influenza virus Matrix Protein M1 preserves its conformation with pH, changing multimerization state at the priming stage due to electrostatics

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

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