Mechanisms of cell entry by influenza virus

Cross, KJ; Burleigh, Laura; Steinhauer, David A.

doi:10.1017/s1462399401003453

Cited by 62 publications

(68 citation statements)

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“…fusion protein refolding | membrane fusion | electron microscopy E nveloped viruses such as influenza virus, human immunodeficiency virus (HIV), and parainfluenza virus 5 (PIV5) encode class I fusion proteins that mediate coalescence of the viral and target membranes (1)(2)(3)(4)(5)(6). Homotrimeric class I fusion proteins are synthesized as biologically inactive precursors that are activated by proteolytic cleavage, which generates a new N-terminal hydrophobic sequence known as the fusion peptide.…”

mentioning

confidence: 99%

Capture and imaging of a prehairpin fusion intermediate of the paramyxovirus PIV5

Kim

Donald

Grigoryan

et al. 2011

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

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During cell entry, enveloped viruses fuse their viral membrane with a cellular membrane in a process driven by energetically favorable, large-scale conformational rearrangements of their fusion proteins. Structures of the pre-and postfusion states of the fusion proteins including paramyxovirus PIV5 F and influenza virus hemagglutinin suggest that this occurs via two intermediates. Following formation of an initial complex, the proteins structurally elongate, driving a hydrophobic N-terminal "fusion peptide" away from the protein surface into the target membrane. Paradoxically, this first conformation change moves the viral and cellular bilayers further apart. Next, the fusion proteins form a hairpin that drives the two membranes into close opposition. While the pre-and postfusion hairpin forms have been characterized crystallographically, the transiently extended prehairpin intermediate has not been visualized. To provide evidence for this extended intermediate we measured the interbilayer spacing of a paramyxovirus trapped in the process of fusing with solid-supported bilayers. A goldlabeled peptide that binds the prehairpin intermediate was used to stabilize and specifically image F-proteins in the prehairpin intermediate. The interbilayer spacing is precisely that predicted from a computational model of the prehairpin, providing strong evidence for its structure and functional role. Moreover, the F-proteins in the prehairpin conformation preferentially localize to a patch between the target and viral membranes, consistent with the fact that the formation of the prehairpin is triggered by local contacts between F-and neighboring viral receptor-binding proteins (HN) only when HN binds lipids in its target membrane.fusion protein refolding | membrane fusion | electron microscopy E nveloped viruses such as influenza virus, human immunodeficiency virus (HIV), and parainfluenza virus 5 (PIV5) encode class I fusion proteins that mediate coalescence of the viral and target membranes (1-6). Homotrimeric class I fusion proteins are synthesized as biologically inactive precursors that are activated by proteolytic cleavage, which generates a new N-terminal hydrophobic sequence known as the fusion peptide. The crystal structures of the paramyxovirus F-protein in its metastable prefusion form and the human parainfluenza virus 3 (hPIV3) F-protein in its very stable postfusion form, and also the influenza virus HA in pre-and postfusion conformations, reveal a unique protein architecture that undergoes large-scale, irreversible refolding during membrane fusion (7-10).These structures provided snapshots of the locations of the critical fusion peptide in the initial and final states: In the prefusion form, the fusion peptide is located along the protein surface, near the virus membrane; while in the postfusion state it is positioned to penetrate into the viral membrane through the formation of a hairpin conformation. Nevertheless, photochemical labeling (11) indicates that the fusion peptide engages with the target membrane in ...

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mentioning

confidence: 99%

Capture and imaging of a prehairpin fusion intermediate of the paramyxovirus PIV5

Kim

Donald

Grigoryan

et al. 2011

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

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“…Later, more aa substitutions in HA infl uencing the pH optimum of fusion in vitro were reported (Daniels et al, 1985;Steinhauer et al, 1995;Hoff man et al, 1997;Cross et al, 2001;Th oennes et al, 2008;Xu and Wilson, 2011) (Table 1 , Fig. 4).…”

Section: Fusion Activation Ph As a Determinant Of Iav Virulencementioning

confidence: 95%

“…Th e heavy chain, HA1 gp, forms the globular head of HA trimer with the receptor binding site (RBS), which is highly conserved among all IAVs. It is composed of aa in positions 98Y, 153W, 183H and 195Y (Cross et al, 2001). Th ese amino acids contribute to the preservation of RBS structure.…”

Section: Structure and Function Of Hemagglutininmentioning

confidence: 99%

“…Th ese amino acids contribute to the preservation of RBS structure. Th ree of them (except 195Y) are directly involved in the virus binding to cell surface receptors (Cross et al, 2001). Th e virus attachment to cell receptors is infl uenced also by variable amino acids surrounding RBS (Isin et al, 2002).…”

Section: Structure and Function Of Hemagglutininmentioning

confidence: 99%

“…It was confi rmed that amino acids in positions 226 and 228 on HA1 gp are responsible for this preference of virus binding. When aa glutamine or glycin are present in these positions, the IAV binding to Sial(α-2,3)Gal linkage is preferred, while Sial(α-2,6)Gal linkage is preferred when leucin or serin are in these positions (Connor et al, 1994;Cross et al, 2001). In the upper respiratory tract of humans prevail the epithelial cells with α-2,6 terminally-linked SA receptors.…”

Section: Receptor Binding Activity and Iav Host Tropismmentioning

confidence: 99%

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The role of fusion activity of influenza A viruses in their biological properties

Jakubcová¹,

Hollý²,

Varečková³

2016

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Summary. -Infl uenza A viruses (IAVs) cause acute respiratory infections of humans, which are repeated yearly. Human IAV infections are associated with signifi cant morbidity and mortality and therefore they represent a serious health problem. All human IAV strains are originally derived from avian IAVs, which, aft er their adaptation to humans, can spread in the human population and cause pandemics with more or less severe course of the disease. Presently, however, the potential of avian IAV to infect humans and to cause the disease cannot be predicted. Many studies are therefore focused on factors infl uencing the virulence and pathogenicity of IAV viruses in a given host. Th e virus-host interaction starts by virus attachment via the envelope glycoprotein hemagglutinin (HA) to the receptors on the cell surface. In addition to receptor binding, HA mediates also the fusion of viral and endosomal membranes, which follows the virus endocytosis. Th e fusion potential of HA trimer, primed by proteolytic cleavage, is activated by low pH in endosomes, resulting in HA refolding into the fusion-active form. Th e HA conformation change is predetermined by its 3-D structure, is pH-dependent, irreversible and strain-specifi c. Th e process of fusion activation of IAV hemagglutinin is crucial for virus entry into the cell and for the ability of the virus to replicate in the host. Here we discuss the known data about the characteristics of fusion activation of HA in relation to IAV virulence and pathogenicity.Keywords: infl uenza A viruses; pH optimum of fusion; IAV virulence and pathogenicity; HA conformation change; IAV interspecies transmission; adaptation changes * Corresponding author. E-mail: viruevar@savba.sk; phone: 421-2-59302427. Abbreviations: HA = hemagglutinin; HA0 = HA precursor; HA1 = heavy chain of HA; HA2 = light chain of HA; HPAI = highly pathogenic avian infl uenza; IAV(s) = infl uenza A virus(es); LPAI = low pathogenic avian infl uenza; M1 protein = matrix protein; mRNA = messenger RNA; NA = neuraminidase; NEP protein = nuclear export protein; NS1 protein = nonstructural protein 1; PA = polymerase acidic protein; PB1 = polymerase basic protein 1; PB2 = polymerase basic protein 2; RBS = receptor binding site; RNA = ribonucleic acid; RNP = ribonucleoprotein; SA = sialic acid; vRNA = viral RNA Content: 1. Introduction 2. Structure and function of hemagglutinin 2.1 Receptor binding activity and IAV host tropism 2.2 Fusion activity and structural rearrangements of HA during the membrane fusion 3. Th e HA cleavability by host proteases and HA fusion activation pH as factors of IAV virulence and pathogenicity 3.1 Cleavage activation of HA as a determinant of IAV pathogenicity 3.2 Fusion activation pH as a determinant of IAV virulence 4. Th e role of fusion activation pH and stability of HA in the adaptation of IAV to the new host 5. Other viral proteins infl uencing the IAV virulence 6. Conclusion

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