Comparative structural analysis of haemagglutinin proteins from type A influenza viruses: conserved and variable features

BMC Bioinformatics

Irene Righetto²  Adelaide Milani¹  Giovanni Cattoli¹  Francesco Filippini² 

[1] FAO-OIE and National Reference Laboratory for Newcastle Disease and Avian Influenza, Istituto Zooprofilattico delle Venezie (IZSVe), viale dell’Università 10, Legnaro, 35020, Italy

[2] Molecular Biology and Bioinformatics Unit (MOLBINFO), Department of Biology, University of Padua, via U. Bassi 58/B, Padova, 35131, Italy

关键词: Hydropathy analysis;    Isopotential contour;    Homology modeling;    Receptor binding domain;    Antigenic drift;    H5N1;    Viral evolution;    Avian influenza virus;    Haemagglutinin;   

Others  :  1084578
DOI  :  10.1186/s12859-014-0363-5

 received in 2014-07-14, accepted in 2014-10-28,  发布年份 2014

【 摘 要 】

Background

Genome variation is very high in influenza A viruses. However, viral evolution and spreading is strongly influenced by immunogenic features and capacity to bind host cells, depending in turn on the two major capsidic proteins. Therefore, such viruses are classified based on haemagglutinin and neuraminidase types, e.g. H5N1. Current analyses of viral evolution are based on serological and primary sequence comparison; however, comparative structural analysis of capsidic proteins can provide functional insights on surface regions possibly crucial to antigenicity and cell binding.

Results

We performed extensive structural comparison of influenza virus haemagglutinins and of their domains and subregions to investigate type- and/or domain-specific variation. We found that structural closeness and primary sequence similarity are not always tightly related; moreover, type-specific features could be inferred when comparing surface properties of haemagglutinin subregions, monomers and trimers, in terms of electrostatics and hydropathy. Focusing on H5N1, we found that variation at the receptor binding domain surface intriguingly relates to branching of still circulating clades from those ones that are no longer circulating.

Conclusions

Evidence from this work suggests that integrating phylogenetic and serological analyses by extensive structural comparison can help in understanding the ‘functional evolution’ of viral surface determinants. In particular, variation in electrostatic and hydropathy patches can provide molecular evolution markers: intriguing surface charge redistribution characterizing the haemagglutinin receptor binding domains from circulating H5N1 clades 2 and 7 might have contributed to antigenic escape hence to their evolutionary success and spreading.

【 授权许可】

   
2014 Righetto et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】

• [1]Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M, Throsby M, Goudsmit J, Wilson IA: Antibody recognition of a highly conserved influenza virus epitope. Science 2009, 324:246-251.
• [2]Han T, Marasco WA: Structural basis of influenza virus neutralization. Ann N Y Acad Sci 2011, 1217:178-190.
• [3][http://www.who.int/research/en/] webcite World Health Organization []
• [4][http://www.cdc.gov/datastatistics/] webcite Center for Disease Control and prevention []
• [5]Hamilton BS, Whittaker GR, Daniel S: Influenza virus-mediated membrane fusion: determinants of hemagglutinin fusogenic activity and experimental approaches for assessing virus fusion. Viruses 2012, 4:1144-1168.
• [6]Sriwilaijaroen N, Suzuki Y: Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. Proc Jpn Acad Ser B Phys Biol Sci 2012, 88:226-249.
• [7]Velkov T, Ong C, Baker MA, Kim H, Li J, Nation RL, Huang JX, Cooper MA, Rockman S: The antigenic architecture of the hemagglutinin of influenza H5N1 viruses. Mol Immunol 2013, 56:705-719.
• [8]Stanekova Z, Vareckova E: Conserved epitopes of influenza A virus inducing protective immunity and their prospects for universal vaccine development. Virol J 2010, 7:351. BioMed Central Full Text
• [9]Russell RJ, Gamblin SJ, Haire LF, Stevens DJ, Xiao B, Ha Y, Skehel JJ: H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 2004, 325:287-296.
• [10]Gamblin SJ, Skehel JJ: Influenza haemagglutinin and neuraminidase membrane glycoproteins. J Biol Chem 2010, 285:28403-28409.
• [11]Gamblin SJ, Haire LF, Russell RJ, Stevens DJ, Xiao B, Ha Y, Vasisht N, Steinhauer DA, Daniels RS, Elliot A, Wiley DC, Skehel JJ: The structure and receptor binding properties of the 1918 influenza haemagglutinin. Science 2004, 303:1838-1842.
• [12]Xu R, Wilson IA: Structural characterization of an early fusion intermediate of influenza virus haemagglutinin. J Virol 2011, 85:5172-5182.
• [13]Sauter NK, Hanson JE, Glick GD, Brown JH, Crowther RL, Park SJ, Skehel JJ, Wiley DC: Binding of influenza virus haemagglutinin to analogs of its cell-surface receptor, sialic acid: analysis by proton nuclear magnetic resonance spectroscopy and X-ray crystallography. Biochemistry 1992, 31:9609-9621.
• [14]DuBois RM, Zaraket H, Reddivari M, Heath RJ, White SW, Russell CJ: Acid stability of the haemagglutinin protein regulates H5N1 influenza virus pathogenicity. PLoS Pathog 2011, 7(12):e1002398.
• [15]Ha Y, Stevens DJ, Skehel JJ, Wiley DC: H5 avian and H9 swine influenza virus haemagglutinin structures: possible origin of influenza subtypes. EMBO J 2002, 21:865-875.
• [16]Lu X, Shi Y, Gao F, Xiao H, Wang M, Qi J, Gao GF: Insights into avian influenza virus pathogenicity: the haemagglutinin precursor HA0 of subtype H16 has an alpha-helix structure in its cleavage site with inefficient HA1/HA2 cleavage. J Virol 2012, 86:12861-12870.
• [17]Carugo O, Pongor S: A normalized root mean square distance for comparing protein three dimensional structures. Protein Sci 2001, 10:1470-1473.
• [18]Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE: UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 2004, 25:1605-1612.
• [19]Wang W, Anderson CM, De Feo CJ, Zhuang M, Yang H, Vassell R, Xie H, Ye Z, Scott D, Weiss CD: Cross-neutralizing antibodies to pandemic 2009 H1N1 and recent seasonal H1N1 influenza A strains influenced by a mutation in haemagglutinin subunit 2. PLoS Pathog 2011, 7(6):e1002081.
• [20]Chothia C, Lesk AM: The relation between the divergence of sequence and structure in proteins. EMBO J 1986, 5:823-826.
• [21]De Franceschi N, Wild K, Schlacht A, Dacks JB, Sinning I, Filippini F: Longin and GAF domains: structural evolution and adaptation to the subcellular trafficking machinery. Traffic 2014, 15:104-121.
• [22]Jang SB, Kim YG, Cho YS, Suh PG, Kim KH, Oh BH: Crystal structure of SEDL and its implications for a genetic disease spondyloepiphyseal displasia tarda. J Biol Chem 2002, 277:49863-49869.
• [23]Jeyabalan J, Nesbit MA, Galvanovskis J, Callaghan R, Rorsman P, Thakker RV: SEDLIN forms omodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1. PLoS One 2010, 5(5):e10646.
• [24]Ekiert DC, Friesen RH, Bhabha G, Kwaks T, Jongeneelen M, Yu W, Ophorst C, Cox F, Korse HJ, Brandenburg B, Vogels R, Brakenhoff JP, Kompier R, Koldijk MH, Cornelissen LA, Poon LL, Peiris M, Koudstaal W, Wilson IA, Goudsmit J: A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 2011, 333:843-850.
• [25]Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA: PDB2PQR: an automated pipeline for the setup, execution, and analysis of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Res 2004, 32(Web server issue):W665-W667.
• [26]Dolinsky TJ, Czodrowski P, Li H, Nielsen JE, Jensen JH, Klebe G, Baker NA: PDB2PQR: Expanding and upgrading automated preparation of biomolecular structures for molecular simulations. Nucleic Acids Res 2007, 35(Web server issue):W522-W525.
• [27]Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA: Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A 2001, 98:10037-10041.
• [28]Richter S, Wenzel A, Stein M, Gabdoulline RR, Wade R: WebPIPSA: a web server for the comparison of protein interaction properties. Nucleic Acid Res 2008, 36(Web Server Issue):W276-W280.
• [29]Hodgkin EE, Richards WG: Molecular similarity based on electrostatic potential and electric field. Int J Quant Chem 1987, 32(Suppl 14):105-110.
• [30]Guo T, Gong LC, Sui SF: An electrostatically preferred lateral orientation of SNARE complex suggests novel mechanisms for driving membrane fusion. PLoS One 2010, 5(1):e8900.
• [31]Lee KK, Fitch CA, Garcìa-Moreno EB: Distance dependence and salt sensitivity of pairwise, coulombic interactions in a protein. Protein Sci 2002, 11:1004-1016.
• [32]López de Victoria A, Kieslich CA, Rizos AK, Krambovitis E, Morikis D: Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties. BMC Biophys 2012, 5:3. BioMed Central Full Text
• [33]Kyte J, Doolittle RF: A simple method for displaying the hydropathic character of a protein. J Mol Biol 1982, 157:105-132.
• [34][http://arbl.cvmbs.colostate.edu/molkit/hydropathy/] webcite Protein Hydrophobicity Plots []
• [35]Bower M, Cohen FE, Dunbrack RL Jr: Sidechain prediction from a backbone-dependent rotamer library: A new tool for homology modeling. J Mol Biol 1997, 267:1268-1282.
• [36]Canutescu AA, Shelenkov AA, Dunbrack RL Jr: A graph theory algorithm for protein side-chain prediction. Protein Sci 2003, 12:2001-2014.
• [37]Xu D, Zhang Y: Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J 2011, 101:2525-2534.
• [38]Gautier R, Camproux AC, Tufféry P: SCit: web tools for protein side chain conformation analysis. Nucleic Acids Res 2004, 32(Web Server issue):W508-W511.
• [39]Benkert P, Künzli M, Schwede T: QMEAN Server for Protein Model Quality Estimation. Nucleic Acids Res 2009, 37(Web Server issue):W510-W514.
• [40]Bordoli L, Kiefer F, Arnold K, Benkert P, Battey J, Schwede T: Protein structure homology modeling using SWISS-MODEL workspace. Nat Protoc 2009, 4(1):1-13.
• [41][http://www.cgl.ucsf.edu/chimera/] webcite UCSF Chimera [ ]
• [42][http://www.poissonboltzmann.org] webcite APBS server []
• [43]Sitkoff D, Sharp K, Honig B: Accurate calculation of hydration free energies using macroscopic solvent models. J Phys Chem 1994, 98:1978-1988.
• [44]Schutz CN, Warshel A: What are the dielectric ‘constants’ of proteins and how to validate electrostatic models? Proteins 2001, 44:400-417.
• [45]Gorham RD Jr, Kieslich CA, Morikis D: Electrostatic clustering and free energy calculations provide a foundation for protein design and optimization. Ann Biomed Eng 2011, 39:1252-1263.
• [46][http://pipsa.eml.org/pipsa] webcite WebPIPSA []
• [47]Gasteiger E, Hoogland C, Gattiker A, Duvaud S, Wilkins MR, Appel RD, Bairoch A: Protein identification and analysis tools on the ExPASy server. In The Proteomics Protocols Handbook. Edited by Walker JM.: Humana Press; 2005:571–607.
• [48][http://www.expasy.org] webcite ExPASy server []