Skip to main content
SpringerLink
Log in

Membrane Fusion and Infection of the Influenza Hemagglutinin

  • Chapter
  • First Online:
Protein Reviews

Part of the book series: Advances in Experimental Medicine and Biology ((PROTRE,volume 966))

Abstract

The influenza virus is a major health concern associated with an estimated 5000 to 30,000 deaths every year (Reed et al. 2015) and a significant economic impact with the development of treatments, vaccinations and research (Molinari et al. 2007). The entirety of the influenza genome is comprised of only eleven coding genes. An enormous degree of variation in non-conserved regions leads to significant challenges in the development of inclusive inhibitors for treatment. The fusion peptide domain of the influenza A hemagglutinin (HA) is a promising candidate for treatment since it is one of the most highly conserved sequences in the influenza genome (Heiny et al. 2007), and it is vital to the viral life cycle. Hemagglutinin is a class I viral fusion protein that catalyzes the membrane fusion process during cellular entry and infection. Impediment of the hemagglutinin’s function, either through incomplete post-translational processing (Klenk et al. 1975; Lazarowitz and Choppin 1975) or through mutations (Cross et al. 2001), leads to non-infective virus particles. This review will investigate current research on the role of hemagglutinin in the virus life cycle, its structural biology and mechanism as well as the central role of the hemagglutinin fusion peptide (HAfp) to influenza membrane fusion and infection.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

BICS:

Bicelle Induced Curvature and Sorting

CD:

Circular Dichroism spectroscopy

DPC:

Dodecylphosphocholine

DOPC:

1,2-dioleoyl-sn-glycero-3-phosphocholine

DOPE:

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

DPoPE:

dipalmitoleoylphosphatidylethanolamine

DSC:

Differential Scanning Calorimetry

EM:

Electron Microscopy

EPR:

Electron Paramagnetic Resonance

FP:

Fusion Peptide

FRET:

Fluorescence Resonance Energy Transfer

FTIR:

Fourier Transform Infrared spectroscopy

HA:

Hemagglutinin

HA0:

Hemagglutinin pre-cleavage precursor

HA1:

Hemagglutinin subunit 1

HA2:

Hemagglutinin subunit 2

HAfp:

Hemagglutinin fusion peptide domain (full-length, 23-residue form)

HAfp20:

Hemagglutinin fusion peptide domain (truncated, 20-residue form)

HA-TMD:

Hemagglutinin transmembrane domain

HII :

type II Hexagonal inverted state

MD:

Molecular Dynamics simulations

NMR:

Nuclear Magnetic Resonance spectroscopy

NA:

Neuraminidase

NGC:

Negative Gaussian Curvature

NOE:

Nuclear Overhauser Effect

PI:

Phosphatidylinositol

PRE:

Paramagnetic Relaxation Enhancement

POPC:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

POPE:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine

POPS:

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine

PS:

Phosphatidylserine

RDC:

Residual Dipolar Coupling

SM:

Sphingomyelin

vRNPs:

viral ribonucleoprotein complexes

References

  • Armstrong RT, Kushnir AS, White JM (2000) The transmembrane domain of influenza hemagglutinin exhibits a stringent length requirement to support the hemifusion to fusion transition. J Cell Biol 151:425–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bax A, Grishaev A (2005) Weak alignment NMR: a hawk-eyed view of biomolecular structure. Curr Opin Struct Biol 15:563–570

    Article  CAS  PubMed  Google Scholar 

  • Biswas S, Yin SR, Blank PS, Zimmerberg J (2008) Cholesterol promotes hemifusion and pore widening in membrane fusion induced by influenza hemagglutinin. J Gen Physiol 131:503–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bowie JU (2011) Membrane protein folding: how important are hydrogen bonds? Curr Opin Struct Biol 21:42–49

    Article  CAS  PubMed  Google Scholar 

  • Brunner J (1989) Testing topological models for the membrane penetration of the fusion peptide of influenza virus hemagglutinin. FEBS Lett 257:369–372

    Article  CAS  PubMed  Google Scholar 

  • Bullough PA, Hughson FM, Skehel JJ, Wiley DC (1994) Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371:37–43

    Article  CAS  PubMed  Google Scholar 

  • Campelo F, McMahon HT, Kozlov MM (2008) The hydrophobic insertion mechanism of membrane curvature generation by proteins. Biophys J 95:2325–2339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carr CM, Chaudhry C, Kim PS (1997) Influenza hemagglutinin is spring-loaded by a metastable native conformation. Proc Natl Acad Sci 94:14306–14313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chakraborty H, Tarafdar PK, Klapper DG, Lentz BR (2013) Wild-type and mutant hemagglutinin fusion peptides alter bilayer structure as well as kinetics and activation thermodynamics of stalk and pore formation differently: mechanistic implications. Biophys J 105:2495–2506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang DK, Cheng SF, Kantchev EA, Lin CH, Liu YT (2008) Membrane interaction and structure of the transmembrane domain of influenza hemagglutinin and its fusion peptide complex. BMC Biol 6:2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chazal N, Gerlier D (2003) Virus Entry, Assembly, Budding, and Membrane Rafts. Microbiol Mol Biol Rev 67:226–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Lee KH, Steinhauer DA, Stevens DJ, Skehel JJ, Wiley DC (1998) Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell 95:409–417

    Article  CAS  PubMed  Google Scholar 

  • Cheng SF, Kantchev AB, Chang DK (2003) Fluorescence evidence for a loose selfassembly of the fusion peptide of influenza virus HA2 in the lipid bilayer. Mol Membr Biol 20:345–351

    Article  CAS  PubMed  Google Scholar 

  • Chernomordik LV, Kozlov MM (2008) Mechanics of membrane fusion. Nat Struct Mol Biol 15:675–683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chernomordik LV, Frolov VA, Leikina E, Bronk P, Zimmerberg J (1998) The pathway of membrane fusion catalyzed by influenza hemagglutinin: restriction of lipids, hemifusion, and lipidic fusion pore formation. J Cell Biol 140:1369–1382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chlanda P, Mekhedov E, Waters H, Schwartz CL, Fischer ER, Ryham RJ, Cohen FS, Blank PS, Zimmerberg J (2016) The hemifusion structure induced by influenza virus haemagglutinin is determined by physical properties of the target membranes. Nat Microbiol 1:16050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collu F, Spiga E, Lorenz CD, Fraternali F (2015) Assembly of Influenza Hemagglutinin Fusion Peptides in a Phospholipid Bilayer by Coarse-grained Computer Simulations. Front Mol Biosci 2:66

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Colotto A, Epand RM (1997) Structural study of the relationship between the rate of membrane fusion and the ability of the fusion peptide of influenza virus to perturb bilayers. Biochemistry 36:7644–7651

    Article  CAS  PubMed  Google Scholar 

  • Cross KJ, Wharton SA, Skehel JJ, Wiley DC, Steinhauer DA (2001) Studies on influenza haemagglutinin fusion peptide mutants generated by reverse genetics. EMBO J 20:4432–4442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cross KJ, Langley WA, Russell RJ, Skehel JJ, Steinhauer DA (2009) Composition and functions of the influenza fusion peptide. Protein Pept Lett 16:766–778

    Article  CAS  PubMed  Google Scholar 

  • Danieli T, Pelletier S, Henis Y, White J (1996) Membrane fusion mediate by the influenza virus hemagglutinin requires the concerted action of at least three hemagglutinin trimers. J Cell Biol 133:559–569

    Article  CAS  PubMed  Google Scholar 

  • De Planque MR, Bonev BB, Demmers JA, Greathouse DV, Koeppe RE, Separovic F, Watts A, Killian JA (2003) Interfacial anchor properties of tryptophan residues in transmembrane peptides can dominate over hydrophobic matching effects in peptide-lipid interactions. Biochemistry 42:5341–5348

    Article  CAS  PubMed  Google Scholar 

  • Di Lella S, Herrmann A, Mair CM (2016) Modulation of the pH stability of influenza virus hemagglutinin: a host cell adaptation strategy. Biophys J 110:2293–2301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Domanska MK, Wrona D, Kasson PM (2013) Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles. Biophys J 105:1383–1387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Domanska MK, Dunning RA, Dryden KA, Zawada KE, Yeager M, Kasson PM (2015) Hemagglutinin Spatial Distribution Shifts in Response to Cholesterol in the Influenza Viral Envelope. Biophys J 109:1917–1924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doms RW, Helenius A (1986) Quaternary structure of influenza virus hemagglutinin after acid treatment. J Virol 60:833–839

    CAS  PubMed  PubMed Central  Google Scholar 

  • Doxsey SJ, Sambrook J, Helenius A, White J (1985) An Efficient Method for Introducing Macromolecules into Living Cells. J Cell Biol 101:19–27

    Article  CAS  PubMed  Google Scholar 

  • Draney AW, Smrt ST, Lorieau JL (2014) Use of isotropically tumbling bicelles to measure curvature induced by membrane components. Langmuir 30:11723–11733

    Article  CAS  PubMed  Google Scholar 

  • Durrer P, Galli C, Hoenke S, Corti C (1996) H+-induced membrane insertion of influenza virus hemagglutinin involves the HA2 amino-terminal fusion peptide but not the coiled coil region. J Biol Chem 271:13417–13421

    Article  CAS  PubMed  Google Scholar 

  • Eichmann C, Orts J, Tzitzilonis C, Vögeli B, Smrt S, Lorieau J, Riek R (2014) Intermolecular Detergent-Membrane Protein NOEs for the Characterization of the Dynamics of Membrane Protein-Detergent Complexes. J Phys Chem B 118:14288–14301

    Article  CAS  PubMed  Google Scholar 

  • Eierhoff T, Hrincius ER, Rescher U, Ludwig S, Ehrhardt C (2010) The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. PLoS Pathog 6(9):e1001099

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ellens H, Bentz J, Szoka FC (1985) H+- and Ca2+-induced fusion and destabilization of liposomes. Biochemistry 24:3099–3106

    Article  CAS  PubMed  Google Scholar 

  • Epand RM, Epand RF (1994) Relationship between the infectivity of influenza virus and the ability of its fusion peptide to perturb bilayers. Biochem Biophys Res Commun 202:1420–1425

    Article  CAS  PubMed  Google Scholar 

  • Epand RM, Epand RF (2000) Modulation of membrane curvature by peptides. Biopolymers 55:358–363

    Article  CAS  PubMed  Google Scholar 

  • Epand R, Shai Y, Segrest JP, Anantharamaiah GM (1995) Mechanisms for the modulation of membrane bilayer properties by amphipathic helical peptides. Biopolymers 37:319–338

    Article  CAS  PubMed  Google Scholar 

  • Epand RM, Epand RF, Martin I, Ruysschaert JM (2001) Membrane interactions of mutated forms of the influenza fusion peptide. Biochemistry 40:8800–8807

    Article  CAS  PubMed  Google Scholar 

  • Fuhrmans M, Marrink SJ (2012) Molecular view of the role of fusion peptides in promoting positive membrane curvature. J Am Chem Soc 134:1543–1552

    Article  CAS  PubMed  Google Scholar 

  • Ge M, Freed JH (2011) Two conserved residues are important for inducing highly ordered membrane domains by the transmembrane domain of influenza hemagglutinin. Biophys J 100:90–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerl MJ, Sampaio JL, Urban S, Kalvodova L, Verbavatz JM, Binnington B, Lindemann D, Lingwood CA, Shevchenko A, Schroeder C, Simons K (2012) Quantitative analysis of the lipidomes of the influenza virus envelope and MDCK cell apical membrane. J Cell Biol 196:213–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gething MJ, Doms RW, York D, White J (1986) Studies on the mechanism of membrane fusion: site-specific mutagenesis of the hemagglutinin of influenza virus. J Cell Biol 102:11–23

    Article  CAS  PubMed  Google Scholar 

  • Ghosh U, Xie L, Weliky DP (2013) Detection of closed influenza virus hemagglutinin fusion peptide structures in membranes by backbone (13)CO- (15)N rotational-echo double-resonance solidstate NMR. J Biomol NMR 55:139–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghosh U, Xie L, Jia L, Liang S, Weliky DP (2015) Closed and semiclosed interhelical structures in membrane vs closed and open structures in detergent for the influenza virus hemagglutinin fusion peptide and correlation of hydrophobic surface area with fusion catalysis. J Am Chem Soc 137:7548–7551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gottschalk A (1957) Neuraminidase: the specific enzyme of influenza virus and Vibrio cholerae. Biochim Biophys Acta 23:645–646

    Article  CAS  PubMed  Google Scholar 

  • Gui L, Ebner JL, Mileant A, Williams JA, Lee KK (2016) Visualization and sequencing of membrane remodeling leading to influenza virus fusion. J Virol 90:6948–6962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han X, Tamm LK (2000) A host – guest system to study structure – function relationships of membrane fusion peptides. Proc Natl Acad Sci 97:13097–13102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han X, Steinhauer DA, Wharton SA, Tamm LK (1999) Interaction of mutant influenza virus hemagglutinin fusion peptides with lipid bilayers: probing the role of hydrophobic residue size in the central region of the fusion peptide. Biochemistry 38:15052–15059

    Article  CAS  PubMed  Google Scholar 

  • Han X, Bushweller JH, Cafiso DS, Tamm LK (2001) Membrane structure and fusiontriggering conformational change of the fusion domain from influenza hemagglutinin. Nat Struct Biol 8:715–720

    Article  CAS  PubMed  Google Scholar 

  • Haque M, Lentz B (2004) Roles of curvature and hydrophobic interstice energy in fusion: studies of lipid perturbant effects. Biochemistry 43:3507–3517

    Article  CAS  PubMed  Google Scholar 

  • Haria NR, Monticelli L, Fraternali F, Lorenz CD (2014) Plasticity and conformational equilibria of influenza fusion peptides in model lipid bilayers. Biochim Biophys Acta Biomembr 1838:1169–1179

    Article  CAS  Google Scholar 

  • Harter C, James P, Bachi T, Semenza G, Brunner J (1989) Hydrophobic binding of the ectodomain of influenza hemagglutinin to membranes occurs through the “fusion peptide”. J Biol Chem 264:6459–6464

    CAS  PubMed  Google Scholar 

  • Heiny AT, Miotto O, Srinivasan KN, Khan AM, Zhang GL, Brusic V, Tan TW, August JT (2007) Evolutionarily conserved protein sequences of influenza a viruses, avian and human, as vaccine targets. PLoS One 2(11):e1190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hernandez JM, Stein A, Behrmann E, Riedel D, Cypionka A, Farsi Z, Walla PJ, Raunser S, Jahn R (2012) Membrane fusion intermediates via directional and full assembly of the SNARE complex. Science 336:1581–1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heuvingh J, Pincet F, Cribier S (2004) Hemifusion and fusion of giant vesicles induced by reduction of inter-membrane distance. Eur Phys J E 14:269–276

    Article  CAS  PubMed  Google Scholar 

  • Hoekstra D, de Boer T, Klappe K, Wilschut J (1984) Fluorescence Method for Measuring the Kinetics of Fusion. Biochemistry 23:5675–5681

    Article  CAS  PubMed  Google Scholar 

  • Ishiguro R, Kimura N, Takahashi S (1993) Orientation of fusion-active synthetic peptides in phospholipid bilayers: determination by Fourier transform infrared spectroscopy. Biochemistry 32:9792–9797

    Article  CAS  PubMed  Google Scholar 

  • Ivanovic T, Choi JL, Whelan SP, van Oijen AM, Harrison SC (2013) Influenza-virus membrane fusion by cooperative fold-back of stochastically induced hemagglutinin intermediates. Elife 2013:1–20

    Google Scholar 

  • Kanaseki T, Kawasaki K, Murata M, Ikeuchi Y, Ohnishi SI (1997) Structural features of membrane fusion between influenza virus and liposome as revealed by quick-freezing electron microscopy. J Cell Biol 137:1041–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kasson PM, Lindahl E, Pande VS (2010) Atomic-resolution simulations predict a transition state for vesicle fusion defined by contact of a few lipid tails. PLoS Comput Biol 6:1–11

    Article  CAS  Google Scholar 

  • Katz G, Benkarroum Y, Wei H, Rice WJ, Bucher D, Alimova A, Katz A, Klukowska J, Herman GT, Gottlieb P (2014) Morphology of influenza B/lee/40 determined by cryo-electron microscopy. PLoS One 9(2):e88288

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kemble GW, Danieli T, White JM (1994) Lipid-anchored influenza hemagglutinin promotes hemifusion, not complete fusion. Cell 76:383–391

    Article  CAS  PubMed  Google Scholar 

  • Klenk H, Rott R, Orlich M, Blödorn J (1975) Activation of influenza A viruses by trypsin treatment. Virology 68:426–439

    Article  CAS  PubMed  Google Scholar 

  • Kozlov MM, Markin VS (1983) Possible mechanism of membrane fusion. Biofizika 28:242–247

    CAS  PubMed  Google Scholar 

  • Kozlov MM, Markin VS (1984) On the theory of membrane fusion. The adhesioncondensation mechanism. Gen Physiol Biophys 3:379–402

    CAS  PubMed  Google Scholar 

  • Kozlovsky Y, Kozlov MM (2002) Stalk model of membrane fusion: solution of energy crisis. Biophys J 82:882–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kozlovsky Y, Chernomordik LV, Kozlov MM (2002) Lipid intermediates in membrane fusion: formation, structure, and decay of hemifusion diaphragm. Biophys J 83:2634–2651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai AL, Freed JH (2015) The interaction between influenza HA fusion peptide and transmembrane domain affects membrane structure. Biophys J 109:2523–2536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai AL, Park H, White JM, Tamm LK (2006a) Fusion peptide of influenza hemagglutinin requires a fixed angle boomerang structure for activity. J Biol Chem 281:5760–5770

    Article  CAS  PubMed  Google Scholar 

  • Langley WA, Thoennes S, Bradley KC, Galloway SE, Talekar GR, Cummings SF, Varecková E, Russell RJ, Steinhauer DA (2009) Single residue deletions along the length of the influenza HA fusion peptide lead to inhibition of membrane fusion function. Virology 394:321–330

    Article  CAS  PubMed  Google Scholar 

  • Langosch D, Hofmann M, Ungermann C (2007) The role of transmembrane domains in membrane fusion. Cell Mol Life Sci 64:850–864

    Article  CAS  PubMed  Google Scholar 

  • Larsson P, Kasson PM (2013) Lipid tail protrusion in simulations predicts fusogenic activity of influenza fusion peptide mutants and conformational models. PLoS Comput Biol 9:e1002950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lazarowitz SG, Choppin PW (1975) Enhancement of the infectivity of influenza A and B viruses by proteolytic cleavage of the hemagglutinin polypeptide. Virology 68:440–454

    Article  CAS  PubMed  Google Scholar 

  • Lear JD, DeGrado WF (1987) Membrane binding and conformational properties of peptides representing the NH2 terminus of influenza HA-2. J Biol Chem 262:6500–6505

    CAS  PubMed  Google Scholar 

  • Lee DW, Thapar V, Clancy P, Daniel S (2014) Stochastic fusion simulations and experiments suggest passive and active roles of hemagglutinin during membrane fusion. Biophys J 106:843–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Légaré S, Lagüe P (2012) The influenza fusion peptide adopts a flexible flat v conformation in membranes. Biophys J 102:2270–2278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leikin S, Kozlov MM, Fuller NL, Rand RP (1996) Measured effects of diacylglycerol on structural and elastic properties of phospholipid membranes. Biophys J 71:2623–2632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Han X, Lai AL, Bushweller JH, Cafiso DS, Tamm LK (2005) Membrane structures of the hemifusion-inducing fusion peptide mutant G1S and the fusion-blocking mutant G1V of influenza virus hemagglutinin suggest a mechanism for pore opening in membrane fusion. J Virol 79:12065–12076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Das P, Zhou R (2010) Single mutation effects on conformational change and membrane deformation of influenza hemagglutinin fusion peptides. J Phys Chem B 114:8799–8806

    Article  CAS  PubMed  Google Scholar 

  • Liu H, Spielmann HP, Ulyanov NB, Wemmer DE, James TL (1995) Interproton distance bounds from 2D NOE intensities: effect of experimental noise and peak integration errors. J Biomol NMR 6:390–402

    Article  CAS  PubMed  Google Scholar 

  • Longo ML, Waring AJ, DA H (1997) Interaction of the influenza hemagglutinin fusion peptide with lipid bilayers: area expansion and permeation. Biophys J 73:1430–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorieau JL, Louis JM, Bax A (2010) The complete influenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface. Proc Natl Acad Sci U S A 107:11341–11346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorieau JL, Louis JM, Bax A (2011a) Helical hairpin structure of influenza hemagglutinin fusion peptide stabilized by charge− dipole interactions between the N-Terminal Amino Group and the Second. J Am Chem Soc 133:2824–2827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorieau JL, Louis JM, Bax A (2011b) Whole-body rocking motion of a fusion peptide in lipid bilayers from size-dispersed 15N NMR relaxation. J Am Chem Soc 133:14184–14187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorieau JL, Louis JM, Schwieters CD, Bax A (2012) pH-triggered, activated-state conformations of the influenza hemagglutinin fusion peptide revealed by NMR. Proc Natl Acad Sci U S A 109:19994–19999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorieau JL, Louis JM, Bax A (2013) The impact of influenza hemagglutinin fusion peptide length and viral subtype on its structure and dynamics. Biopolymers 99:189–195

    Article  CAS  PubMed  Google Scholar 

  • Luneberg J, Martin I, Nussler F, Ruysschaert JM, Herrmann A (1995) Structure and topology of the influenza virus fusion peptide in lipid bilayers. J Biol Chem 270:27606–27614

    Article  CAS  PubMed  Google Scholar 

  • Macosko JC, Kim CH, Shin YK (1997) The membrane topology of the fusion peptide region of influenza hemagglutinin determined by spin-labeling EPR. J Mol Biol 267:1139–1148

    Article  CAS  PubMed  Google Scholar 

  • Markin VS, Albanesi JP (2002) Membrane fusion: stalk model revisited. Biophys J 82:693–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Markovic I, Leikina E, Zhukovsky M, Zimmerberg J, Chernomordik LV (2001) Synchronized activation and refolding of influenza hemagglutinin in multimeric fusion machines. J Cell Biol 155:833–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marsh M (1984) The entry of enveloped viruses into cells by endocytosis. Biochem J 218:1–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matlin KS, Reggio H, Helenius A, Simons K (1981) Infectious Entry Pathway of Influenza-Virus in A Canine Kidney-Cell Line. J Cell Biol 91:601–613

    Article  CAS  PubMed  Google Scholar 

  • Melikyan GB, Niles WD, Peeples ME, Cohen FS (1993a) Influenza hemagglutinin- mediated fusion pores connecting cells to planar membranes: flickering to final expansion. J Gen Physiol 102:1131–1149

    Article  CAS  PubMed  Google Scholar 

  • Melikyan GB, Niles WD, Cohen FS (1993b) Influenza virus hemagglutinin-induced cellplanar bilayer fusion: quantitative dissection of fusion pore kinetics into stages. J Gen Physiol 102:1151–1170

    Article  CAS  PubMed  Google Scholar 

  • Melikyan GB, Niles WD, Ratinov VA, Karhanek M, Zimmerberg J, Cohen FS (1995) Comparison of transient and successful fusion pores connecting influenza hemagglutinin expressing cells to planar membranes. J Gen Physiol 106:803–819

    Article  CAS  PubMed  Google Scholar 

  • Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, Bridges CB (2007) The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine 25:5086–5096

    Article  PubMed  Google Scholar 

  • Morgan C, Rose HM (1968) Structure and Development of Viruses as Observed in the Electron Microscope: VIII. Entry of Influenza Virus J Virol 2:925–936

    CAS  PubMed  Google Scholar 

  • Munster VJ, Baas C, Lexmond P, Waldenström J, Wallensten A, Fransson T, Rimmelzwaan GF, Beyer WEP, Schutten M, Olsen B, Osterhaus AD, Fouchier RA (2007) Spatial, temporal, and species variation in prevalence of influenza A viruses in wild migratory birds. PLoS Pathog 3:0630–0638

    Article  CAS  Google Scholar 

  • Murata M, Sugahara Y, Ohnishi S, Takahashi S (1987) pH-Dependent Membrane Fusion Activity of a Synthetic Twenty Amino Acid Peptide with the Same Sequence as That of the Hydrophobic Segment of Influenza Virus Hemagglutinin. J Biochem 102:957–962

    Article  CAS  PubMed  Google Scholar 

  • Nayak DP, Hui EK, Barman S (2004) Assembly and budding of influenza virus. Virus Res 106:147–165

    Article  CAS  PubMed  Google Scholar 

  • Nikolaus J, Scolari S, Bayraktarov E, Jungnick N, Engel S, Plazzo AP, Stöckl M, Volkmer R, Veit M, Herrmann A (2010) Hemagglutinin of influenza virus partitions into the nonraft domain of model membranes. Biophys J 99:489–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niles WD, Cohen FS (1993) Single event recording shows that docking onto receptor alters the kinetics of membrane fusion mediated by influenza hemagglutinin. Biophys J 65:171–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plonsky I, Kingsley DH, Rashtian A, Blank PS, Zimmerberg J (2008) Initial size and dynamics of viral fusion pores are a function of the fusion protein mediating membrane fusion. Biol Cell 100:377–386

    Article  CAS  PubMed  Google Scholar 

  • Polozov IV, Bezrukov L, Gawrisch K, Zimmerberg J (2008) Progressive ordering with decreasing temperature of the phospholipids of influenza virus. Nat Chem Biol 4:248–255

    Article  CAS  PubMed  Google Scholar 

  • Reed C, Chaves SS, Kirley PD, Emerson R, Aragon D, Hancock EB, Butler L, Baumbach J, Hollick G, Bennett NM, Laidler MR, Thomas A, Meltzer MI, Finelli L (2015) Estimating influenza disease burden from population-based surveillance data in the United States. PLoS One 10:1–13

    CAS  Google Scholar 

  • Ridder AN, Morein S, Stam JG, Kühn A, De Kruijff B, Killian JA (2000) Analysis of the role of interfacial tryptophan residues in controlling the topology of membrane proteins. Biochemistry 39:6521–65286

    Article  CAS  PubMed  Google Scholar 

  • Risselada HJ, Marelli G, Fuhrmans M et al (2012) Line-tension controlled mechanism for influenza fusion. PLoS One 7:E38302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruigrok RW, Wrigley NG, Calder LJ, Cusack S, Wharton SA, Brown EB, Skehel JJ (1986) Electron microscopy of the low pH structure of influenza virus haemagglutinin. EMBO J 5:41–49

    CAS  PubMed  PubMed Central  Google Scholar 

  • Russell RJ, Gamblin SJ, Haire LF, Stevens DJ, Xiao B, Ha Y, Skehel JJ (2004) H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 325:287–296

    Article  CAS  PubMed  Google Scholar 

  • Russier M, Yang G, Rehg JE, Wong S, Mostafa HH, Barman S, Krauss S, Webster RG, Webby RJ, Charles J (2016) Molecular requirements for a pandemic influenza virus: an acidstable hemagglutinin protein. Proc Natl Acad Sci 113:1636–1641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheiffele P, Rietveld A, Simons K, Wilk T (1999) Influenza viruses select ordered lipid membrane influenza viruses select ordered lipid domains during budding from the plasma membrane. J Biol Chem 274:2038–2044

    Article  CAS  PubMed  Google Scholar 

  • Senes A, Ubarretxena-Belandia I, Engelman DM (2001) The Calpha ---H...O hydrogen bond: a determinant of stability and specificity in transmembrane helix interactions. Proc Natl Acad Sci U S A 98:9056–9061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sieczkarski SB, Whittaker GR (2002) Influenza virus can enter and infect cells in the absence of clathrin-mediated endocytosis influenza virus can enter and infect cells in the absence of clathrin-mediated endocytosis. J Virol 76:10455–10464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel D (1993) Energetics of intermediates in membrane fusion: comparison of stalk and inverted micellar intermediate mechanisms. Biophys J 65:2124–2140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel D, Epand R (1997) The mechanism of lamellar-to-inverted hexagonal phase transitions in phosphatidylethanolamine: implications for membrane fusion mechanisms. Biophys J 73:3089–3111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel DP, Epand RM (2000) Effect of influenza hemagglutinin fusion peptide on lamellar/inverted phase transitions in dipalmitoleoylphosphatidylethanolamine: implications for membrane fusion mechanisms. Biochim Biophys Acta 1468:87–98

    Article  CAS  PubMed  Google Scholar 

  • Skehel JJ, Bayley PM, Brown EB, Martin SR, Waterfield MD, White JM, Wilson IA, Wiley DC (1982) Changes in the conformation of influenza virus hemagglutinin at the pH optimum of virus-mediated membrane fusion. Proc Natl Acad Sci U S A 79:968–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smirnova YG, Marrink SJ, Lipowsky R, Knecht V (2010) Solvent-exposed tails as prestalk transition states for membrane fusion at low hydration. J Am Chem Soc 132:6710–6718

    Article  CAS  PubMed  Google Scholar 

  • Smith JC, Derbyshire RB, Cook E, Dunthorne L, Viney J, Brewer SJ, Sassenfeld HM, Bell LD (1984) Chemical synthesis and cloning of a poly(arginine)-coding gene fragment designed to aid polypeptide purification. Gene 32:321–327

    Article  CAS  PubMed  Google Scholar 

  • Smrt ST, Draney AW, Lorieau JL (2015) The influenza hemagglutinin fusion domain is an amphipathic helical hairpin that functions by inducing membrane curvature. J Biol Chem 290:228–238

    Article  CAS  PubMed  Google Scholar 

  • Sodt AJ, Pastor RW (2014) Molecular modeling of lipid membrane curvature induction by a peptide: more than simply shape. Biophys J 106:1958–1969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spruce AE, Iwata A, Almers W (1991) The first milliseconds of the pore formed by a fusogenic viral envelope protein during membrane fusion. Proc Natl Acad Sci U S A 88:3623–3627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stegmann T, Hoekstra D, Scherphof G, Wilschut J (1986) Fusion activity of influenza virus: a comparison between biological and artificial target membrane vesicles. J Biol Chem 261:10966–10969

    CAS  PubMed  Google Scholar 

  • Stegmann T, White JM, Helenius A (1990) Intermediates in influenza induced membrane fusion. EMBO J 9:4231–4241

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stempfer G, Höll-Neugebauer B, Kopetzki E, Rudolph R (1996) A fusion protein designed for noncovalent immobilization: stability, enzymatic activity, and use in an enzyme reactor. Nat Biotechnol 14:481–484

    Article  CAS  PubMed  Google Scholar 

  • Struck DK, Hoekstra D, Pagano RE (1981) Use of resonance energy transfer to monitor membrane fusion. Biochemistry 20:4093–4099

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Weliky DP (2009) 13C-13C correlation spectroscopy of membrane-associated influenza virus fusion peptide strongly supports a helix-turn-helix motif and two turn conformations. J Am Chem Soc 131:13228–13229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sup Kim C, Epand RF, Leikina E, Epand RM, Chernomordik LV (2011) The final conformation of the complete ectodomain of the HA2 subunit of influenza hemagglutinin can by itself drive low pH-dependent fusion. J Biol Chem 286:13226–13234

    Article  CAS  Google Scholar 

  • Tatulian S, Hinterdorfer P, Baber G, Tamm L (1995) Influenza hemagglutinin assumes a tilted conformation during membrane fusion as determined by attenuated total reflection FTIR spectroscopy. EMBO J 14:5514–5523

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tenchov BG, MacDonald RC, Lentz BR (2013) Fusion peptides promote formation of bilayer cubic phases in lipid dispersions. An X-ray diffraction study. Biophys J 104:1029–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thoennes S, Li ZN, Lee BJ, Langley WA, Skehel JJ, Russell RJ, Steinhauer DA (2008) Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusion. Virology 370:403–414

    Article  CAS  PubMed  Google Scholar 

  • Vaccaro L, Cross KJ, Kleinjung J, Straus SK, Thomas DJ, Wharton SA, Skehel JJ, Fraternali F (2005) Plasticity of influenza haemagglutinin fusion peptides and their interaction with lipid bilayers. Biophys J 88:25–36

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Yang L, Huang HW (2007) Evidence of cholesterol accumulated in high curvature regions: implication to the curvature elastic energy for lipid mixtures. Biophys J 92:2819–2830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wasniewski CM, Parkanzky PD, Bodner ML, Weliky DP (2004) Solid-state nuclear magnetic resonance studies of HIV and influenza fusion peptide orientations in membrane bilayers using stacked glass plate samples. Chem Phys Lipids 132:89–100

    Article  CAS  PubMed  Google Scholar 

  • Weber T, Paesold G, Galli C, Mischler R, Semenza G, Brunner J (1994) Evidence for H +- induced insertion of influenza hemagglutinin HA2 N-terminal segment into viral membrane. J Biol Chem 269:18353–18358

    CAS  PubMed  Google Scholar 

  • Wharton SA, Martin SR, Ruigrok RW, Skehel JJ, Wiley DC (1988) Membrane fusion by peptide analogues of influenza virus haemagglutinin. J Gen Virol 69:1847–1857

    Article  CAS  PubMed  Google Scholar 

  • White J, Helenius A, Gething MJ (1982) Haemagglutinin of influenza virus expressed from a cloned gene promotes membrane fusion. Nature 300:658–659

    Article  CAS  PubMed  Google Scholar 

  • Wilson IA, Skehel JJ, Wiley DC (1981) Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289:366–373

    Article  CAS  PubMed  Google Scholar 

  • Wimley WC, Selsted ME, White SH (1994) Interactions between human defensins and lipid bilayers: evidence for formation of multimeric pores. Protein Sci 3:1362–1373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Worch R (2013) The helical hairpin structure of the influenza fusion peptide can be seen on a hydrophobic moment map. FEBS Lett 587:2980–2983

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Parkanzky PD, Bodner ML, Duskin CA, Weliky DP (2002) Application of REDOR subtraction for filtered MAS observation of labeled backbone carbons of membrane-bound fusion peptides. J Magn Reson 159:101–110

    Article  CAS  PubMed  Google Scholar 

  • Yang ST, Kreutzberger AJ, Lee J, Kiessling V, Tamm LK (2016) The role of cholesterol in membrane fusion. Chem Phys Lipids 199:136–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao H, Hong M (2014) Conformation and lipid interaction of the fusion peptide of the paramyxovirus PIV5 in anionic and negative-curvature membranes from solid-state NMR. J Am Chem Soc 136:2611–2624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshimura A, Ohnishi S (1984) Uncoating of influenza virus in endosomes. J Virol 51:497–504

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Neal S, Wishart DS (2003) RefDB: a database of uniformly referenced protein chemical shifts. J Biomol NMR 25:173–195

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Macosko JC, Hughes DW, Sayer BG, Hawes J, Epand RM (2000) 15N NMR study of the ionization properties of the influenza virus fusion peptide in zwitterionic phospholipid dispersions. Biophys J 78:2418–2425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmerberg J, Blumenthal R, Sarkar DE, Curran M, Morris SJ (1994) Restricted movement of lipid and aqueous dyes through pores formed by influenza hemagglutinin during cell fusion. J Cell Biol 127:1885–1894

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA

    Sean T. Smrt & Justin L. Lorieau

Authors
  1. Sean T. Smrt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Justin L. Lorieau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Justin L. Lorieau .

Editor information

Editors and Affiliations

  1. Biochem and Mol Biol, Baylor College of Medicine, Houston, Texas, USA

    M. Zouhair Atassi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Internation Publishing Switzerland

About this chapter

Cite this chapter

Smrt, S.T., Lorieau, J.L. (2016). Membrane Fusion and Infection of the Influenza Hemagglutinin. In: Atassi, M. (eds) Protein Reviews. Advances in Experimental Medicine and Biology(), vol 966. Springer, Singapore. https://doi.org/10.1007/5584_2016_174

Download citation

Publish with us

Policies and ethics

Search

Navigation