Influenza virus M1 protein binds to RNA through its nuclear localization signal.

Elster, Christine; Larsen, Kjeld; Gagnon, Jean; Ruigrok, Rob W.H.; Baudin, Florence

doi:10.1099/0022-1317-78-7-1589

Cited by 83 publications

(74 citation statements)

References 40 publications

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“…However, the mechanism of M1-RNP interaction remains poorly understood. FLUA-M1 has been shown to bind NP (45), RNA (34,36), as well as RNP (4,35,46). In particular, Baudin et al demonstrated that it is the FLUA-M1 C domain, instead of the N domain, that is required for RNP binding (4).…”

Section: Resultsmentioning

confidence: 99%

“…Because FLUA-M1 was reported to nonspecifically bind ssRNA (33,34), we measured the RNA binding affinity of the ISAV-M1 protein using fluorescence polarization assays with synthetic RNA oligos (28). Three RNA oligos of different length (i.e., 12 nt, 24 nt, and 48 nt) were used, but only modest differences were observed in their binding affinities (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

Zhang

Zheng

Toh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.A 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...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

Zhang

Zheng

Toh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…On the one hand, this motif has been proposed to bind zinc (Elster et al, 1994) and play an important role in the virus life cycle, including transcription inhibition by M1 as well as uncoating and virus pathogenesis (Judd et al, 1992(Judd et al, , 1997Nasser et al, 1996;Okada et al, 2003). On the other hand, structural consideration of this region has implied that the CCHH motif may not bind zinc and that neither this region nor its zinc-binding property may be critical in vRNP-binding or in M1-mediated transcription inhibition of the influenza virus vRNP (Watanabe et al, 1996;Elster et al, 1997;Perez & Donis, 1998). Therefore, it became important to define the functional significance of the CCHH motif in virus replication.…”

Section: Discussionmentioning

confidence: 99%

Conserved cysteine and histidine residues in the putative zinc finger motif of the influenza A virus M1 protein are not critical for influenza virus replication

Hui¹,

Ralston²,

Judd³

et al. 2003

Journal of General Virology

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The influenza virus matrix protein (M1) possesses a cysteine and histidine (CCHH) motif in the helix 9 (H9) and adjacent region ( 148 CATCEQIADSQHRSH 162 ). The CCHH motif has been proposed as a putative zinc finger motif and zinc-binding activity has been implicated in virus uncoating as well as transcription inhibition and mRNA regulation. The function of the CCHH motif in the influenza virus life cycle was investigated by site-directed mutagenesis (alanine replacement) and by rescuing mutant viruses by reverse genetics. Mutant viruses containing an alanine replacement of the cysteine and histidine residues, either individually or in combination, were seen to exhibit wt phenotype in multiple virus growth cycles and plaque morphology. In addition, synthetic peptides containing the putative zinc finger motif did not inhibit virus replication in MDCK cells. However, mutation of Ala 155 in H9 was lethal for rescuing infectious virus.These data show that the CCHH motif does not provide a critical function in the influenza virus life cycle in cell culture and that the zinc-binding function may not be involved in virus biology. However, the lethal phenotype of the Ala 155 mutation shows that the H9 region of M1 provides some other critical function(s) in virus replication.

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“…The avian influenza virus can acquire the ability for transmission to humans, mainly as a result of adaptive mutation or genetic reassortment in the strains. Matrix protein 1 (M1), the most abundant structural protein in influenza A virus, consists of 252 amino acids and plays vital roles in the virus life cycle, by regulating the transportation of ribonucleoprotein (RNP) cores into or out of the nucleus [3,4] and controlling the termination of viral RNA synthesis through RNA binding [5,6]. Although being the most conserved in the eight structural proteins, M1 has been frequently observed to exhibit some mutations at several sites, especially in avian H5N1 subtypes [7].…”

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confidence: 99%

Identification of amino acid substitutions in avian influenza virus (H5N1) matrix protein 1 by using nanoelectrospray MS and MS/MS

Liu

Song

Lee

et al. 2009

J. Am. Soc. Mass Spectrom.

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Matrix protein 1 (M1), the major structural protein of the avian influenza virus, plays a critical role in regulation of viral RNA transcription via interaction with RNA and transportation of RNP cores. Mutations in M1 have been frequently observed in the highly virulent avian influenza H5N1 virus, which might be crucial to the pathogenic function. Here we report the characterization of mutated peptides in M1 purified from highly pathogenic avian influenza virus H5N1 by nanoelectrospray MS and MS/MS analyses on a quadrupole-time-of-flight mass spectrometer (Q-TOFMS). The specificity of tandem mass spectrometry allowed the identification of six amino acid (AA) substitutions in M1, including R95K, A166V, I168T, N207S, N224S, and R230K. Two commonly observed modifications such as oxidation and deamidation were accurately assigned in the protein. Bioinformatics analysis suggested some relationship between the amino acid substitution and structural property of M1 protein.Discussions on de novo sequencing of MS/MS spectra, especially in dealing with the AA substitutions, were provided. (J Am Soc Mass Spectrom 2009, 20, 312-320)

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Influenza virus M1 protein binds to RNA through its nuclear localization signal.

Cited by 83 publications

References 40 publications

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

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

Conserved cysteine and histidine residues in the putative zinc finger motif of the influenza A virus M1 protein are not critical for influenza virus replication

Identification of amino acid substitutions in avian influenza virus (H5N1) matrix protein 1 by using nanoelectrospray MS and MS/MS

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