Crystal Structures of Influenza A Virus Matrix Protein M1: Variations on a Theme

Musayev, F.N.; Mosier, Philip D.; Zhou, Qibing; Xie, Hang; Desai, Umesh R.

doi:10.1371/journal.pone.0109510

Cited by 36 publications

(63 citation statements)

References 39 publications

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“…The repulsion between the monomers at pH 5 possibly drives the conformational change in the protein molecule, changing the interacting surface between M1 monomers (16) and explaining the lower surface coverage and the completely differently layered structure of M1 matrix protein under acidic conditions (Fig. 11).…”

Section: Discussionmentioning

confidence: 99%

“…Existing X-ray structures of M1 (14)(15)(16) show that the N-terminal part of M1 forms a dimer. There are small differences at pH 7 and pH 4 within a single protein monomer but completely different interactions between monomers in a dimer (16).…”

mentioning

confidence: 99%

“…There are small differences at pH 7 and pH 4 within a single protein monomer but completely different interactions between monomers in a dimer (16). The main change in the dimer is an alteration of the protein charge with the pH; presumably, electrostatic forces play a pivotal role in these conformational changes in M1.…”

mentioning

confidence: 99%

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pH-Dependent Formation and Disintegration of the Influenza A Virus Protein Scaffold To Provide Tension for Membrane Fusion

Batishchev

Shilova

Kachala

et al. 2016

J Virol

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Influenza virus is taken up from a pH-neutral extracellular milieu into an endosome, whose contents then acidify, causing changes in the viral matrix protein (M1) that coats the inner monolayer of the viral lipid envelope. At a pH of ϳ6, M1 interacts with the viral ribonucleoprotein (RNP) in a putative priming stage; at this stage, the interactions of the M1 scaffold coating the lipid envelope are intact. The M1 coat disintegrates as acidification continues to a pH of ϳ5 to clear a physical path for the viral genome to transit from the viral interior to the cytoplasm. Here we investigated the physicochemical mechanism of M1's pHdependent disintegration. In neutral media, the adsorption of M1 protein on the lipid bilayer was electrostatic in nature and reversible. The energy of the interaction of M1 molecules with each other in M1 dimers was about 10 times as weak as that of the interaction of M1 molecules with the lipid bilayer. Acidification drives conformational changes in M1 molecules due to changes in the M1 charge, leading to alterations in their electrostatic interactions. Dropping the pH from 7.1 to 6.0 did not disturb the M1 layer; dropping it lower partially desorbed M1 because of increased repulsion between M1 monomers still stuck to the membrane. Lipid vesicles coated with M1 demonstrated pH-dependent rupture of the vesicle membrane, presumably because of the tension generated by this repulsive force. Thus, the disruption of the vesicles coincident with M1 protein scaffold disintegration at pH 5 likely stretches the lipid membrane to the point of rupture, promoting fusion pore widening for RNP release. IMPORTANCEInfluenza remains a top killer of human beings throughout the world, in part because of the influenza virus's rapid binding to cells and its uptake into compartments hidden from the immune system. To attack the influenza virus during this time of hiding, we need to understand the physical forces that allow the internalized virus to infect the cell. In particular, we need to know how the protective coat of protein inside the viral surface reacts to the changes in acid that come soon after internalization. We found that acid makes the molecules of the protein coat push each other while they are still stuck to the virus, so that they would like to rip the membrane apart. This ripping force is known to promote membrane fusion, the process by which infection actually occurs. While it is becoming clearer that multiple processes unite to form a pathway for the entry of the influenza virus after its uptake into endosomes, it is not yet clear how and to what extent the pH-driven changes in the viral matrix contribute to that pathway. Influenza virus is an enveloped negative-strand RNA virus of the Orthomyxoviridae family (1). Its outer envelope consists of a host cell-derived bilayer lipid membrane (BLM) with the incorporated glycoproteins hemagglutinin (HA) and neuraminidase along with proton channel M2. The inner envelope of the virion is a membrane-associated scaffold of matrix protein M1, w...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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pH-Dependent Formation and Disintegration of the Influenza A Virus Protein Scaffold To Provide Tension for Membrane Fusion

Batishchev

Shilova

Kachala

et al. 2016

J Virol

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“…The M1 monomer (252 amino acid) is 60 Å long (40), carrying two globular regions-the N-terminal (1-164) and C-terminal (165-252)-linked by a proteasesensitive loop. Crystallographic studies have revealed that the M1 protein is composed of nine a-helices (H1-H9).…”

Section: Introductionmentioning

confidence: 99%

Identification of Conserved Peptides Comprising Multiple T Cell Epitopes of Matrix 1 Protein in H1N1 Influenza Virus

Lohia

Baranwal

2015

Viral Immunology

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Cell mediated immune response plays a key role in combating viral infection and thus identification of new vaccine targets manifesting T cell mediated response may serve as an ideal approach for influenza vaccine. The present study involves the application of an immunoinformatics-based consensus approach for epitope prediction (three epitope prediction tools each for CD4+ and CD8+ T cell epitopes) and molecular docking to identify peptide sequences containing T cell epitopes using the conserved sequences from all the Matrix 1 protein sequences of H1N1 virus available until April 2015. Three peptides comprising CD4+ and CD8+ T cell epitopes were obtained, which were not exactly reported in earlier studies. Population coverage study of these multiepitope peptides revealed that they are capable of inducing a potent immune response belonging to individuals from different populations and ethnicity distributed around the globe. Conservation study with other subtypes of influenza virus infecting humans (H2N2, H5N1, H7N9, and H3N2) revealed that these three peptides were conserved (>90%), with 100% identity in most of these strains. Hence, these peptides can impart immunity against H1N1 as well as other subtypes of influenza virus. A molecular docking study of the predicted peptides with class I and II human leukocyte antigen (HLA) molecules has shown that the majority of them have comparable binding energies to that of native peptides. Hence, these peptides from Matrix 1 protein of H1N1 appear to be promising candidates for universal vaccine design.

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“…The structure of the influenza A virus M1 has been studied extensively by several research groups, but so far only structures of the N-terminal fragment are available (14)(15)(16)(17). Whereas the M1 N domain was found to adopt essentially the same fold in all four reported structures, solution pH appeared to have some effects on its intermolecular interaction, with dimers observed at acidic pH (14) and monomers at neutral pH (15).…”

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confidence: 97%

The crystal structure of an orthomyxovirus matrix protein reveals mechanisms for self-polymerization and membrane association

Tao¹

2017

J Immunol Tech Infect Dis

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Many enveloped viruses encode a matrix protein. In the influenza A virus, the matrix protein M1 polymerizes into a rigid protein layer underneath the viral envelope to help enforce the shape and structural integrity of intact viruses. The influenza virus M1 is also known to mediate virus budding as well as the nuclear export of the viral nucleocapsids and their subsequent packaging into nascent viral particles. Despite extensive studies on the influenza A virus M1 (FLUA-M1), only crystal structures of its N-terminal domain are available. Here we report the crystal structure of the full-length M1 from another orthomyxovirus that infects fish, the infectious salmon anemia virus (ISAV). The structure of ISAV-M1 assumes the shape of an elbow, with its N domain closely resembling that of the FLUA-M1. The C domain, which is connected to the N domain through a flexible linker, is made of four α-helices packed as a tight bundle. In the crystal, ISAV-M1 monomers form infinite 2D arrays with a network of interactions involving both the N and C domains. Results from liposome flotation assays indicated that ISAV-M1 binds membrane via electrostatic interactions that are primarily mediated by a positively charged surface loop from the N domain. Cryoelectron tomography reconstruction of intact ISA virions identified a matrix protein layer adjacent to the inner leaflet of the viral membrane. The physical dimensions of the virion-associated matrix layer are consistent with the 2D ISAV-M1 crystal lattice, suggesting that the crystal lattice is a valid model for studying M1-M1, M1-membrane, and M1-RNP interactions in the virion.ll members of the Orthomyxoviridae family, including the influenza viruses A-D, thogotovirus, and isavirus, encode a matrix protein called M1. In the influenza A virus, M1 is produced by a colinear transcript made from the gene segment 7 (1). As one of the most abundantly made viral proteins, the influenza A virus M1 plays multiple roles during the virus life cycle. Upon viral entry, the acidification of the viral interior in the endosome weakens the interaction between M1 and the viral ribonucleoprotein complexes (vRNPs), thus allowing M1-free vRNPs to be imported to the nucleus for viral RNA replication and transcription (2, 3). As infection proceeds, newly synthesized M1 enters the nucleus to mediate the nuclear export of nascent vRNPs. A "daisy-chain" complex is formed with the vRNP binding to the C-terminal domain of M1 (4) and the N-terminal domain of M1 interacting with the nuclear export protein (NEP), also called NS2. Through its nuclear export signal (NES), NEP is specifically recognized by the cellular exportin Crm1, which then facilitates the transport of vRNPs across the nuclear membrane to the cytoplasm in a RanGTP-dependent manner (5). It has been shown that M1 binding to vRNP in the nucleus is able to block mRNA transcription (4, 6). In the cytosol, M1 interacts with the cytoplasmic tails of the glycoproteins HA and NA. Such interactions promote M1 association with lipid raft membranes and t...

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Crystal Structures of Influenza A Virus Matrix Protein M1: Variations on a Theme

Cited by 36 publications

References 39 publications

pH-Dependent Formation and Disintegration of the Influenza A Virus Protein Scaffold To Provide Tension for Membrane Fusion

pH-Dependent Formation and Disintegration of the Influenza A Virus Protein Scaffold To Provide Tension for Membrane Fusion

Identification of Conserved Peptides Comprising Multiple T Cell Epitopes of Matrix 1 Protein in H1N1 Influenza Virus

The crystal structure of an orthomyxovirus matrix protein reveals mechanisms for self-polymerization and membrane association

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