Structure Of Hemagglutinin Protein Research Articles

Influenza Hemagglutinin Protein Stability, Activation, and Pandemic Risk.

For decades, hemagglutinin (HA) protein structure and its refolding mechanism have served as a paradigm for understanding protein-mediated membrane fusion. HA trimers are in a high-energy state and are functionally activated by low pH. Over the past decade, HA stability (or the pH at which irreversible conformational changes are triggered) has emerged as an important determinant in influenza virus host range, infectivity, transmissibility, and human pandemic potential. Here, we review HA protein structure, assays to measure its stability, measured HA stability values, residues and mutations that regulate its stability, the effect of HA stability on interspecies adaptation and transmissibility, and mechanistic insights into this process. Most importantly, HA stabilization appears to be necessary for adapting emerging influenza viruses to humans.

Genetic and antigenic divergence in the influenza A(H3N2) virus circulating between 2016 and 2017 in Thailand.

Influenza virus evolves rapidly due to the accumulated genetic variations on the viral sequence. Unlike in North America and Europe, influenza season in the tropical Southeast Asia spans both the rainy and cool seasons. Thus, influenza epidemiology and viral evolution sometimes differ from other regions, which affect the ever-changing efficacy of the vaccine. To monitor the current circulating influenza viruses in this region, we determined the predominant influenza virus strains circulating in Thailand between January 2016 and June 2017 by screening 7,228 samples from patients with influenza-like illness. During this time, influenza A(H3N2) virus was the predominant influenza virus detected. We then phylogenetically compared the hemagglutinin (HA) gene from a subset of these A(H3N2) strains (n = 62) to the reference sequences and evaluated amino acid changes in the dominant antigenic epitopes on the HA protein structure. The divergence of the circulating A(H3N2) from the A/Hong Kong/4801/2014 vaccine strain formed five genetic groups (designated I to V) within the 3C.2a clade. Our results suggest a marked drift of the current circulating A(H3N2) strains in Thailand, which collectively contributed to the declining predicted vaccine effectiveness (VE) from 74% in 2016 down to 48% in 2017.

The structural variability of the influenza A hemagglutinin receptor-binding site.

Hemagglutinin (HA) is a transmembrane protein of the influenza A virus and a key component in its life cycle. The protein allows the virus to enter a host cell by recognizing specific glycans attached to transmembrane proteins of the host, which leads to viral endocytosis. In recent years, significant progress has been made in understanding the structural relationship between changes in the HA receptor-binding site (RBS) and the sialylated glycans that bind them. Several mutations were identified in the HA RBS that allows the virus to change host tropism. Their impact on binding the analogs of human and avian receptors was determined with X-ray crystallography. In this article, we provide a short overview of the HA protein structure and briefly discuss the adaptive mutations introduced to different HA subtypes.

Evolutionary Characterization of Human H1N1 Influenza Virus Hemagglutinin Genes Isolated from 1947 to 2009 in China

Objective: Our aim was to reveal the molecular characteristics of human H1N1 influenza virus hemagglutinin (HA) genes from 1947 to 2009 in China. Methods: 129 HA gene sequences were downloaded from NCBI’s GenBank and analyzed by DNASTAR software. Additionally, the three-dimensional structure of HA protein was predicted by the SWISS-MODEL service. Results: First, 2009 Chinese HA genes were 99% identical to those of Mexican and American ones; their key sites remained highly conserved. Second, 50 Chinese strains from 1947 to 2009 clustered by the year of isolation, and 2009 strains had only 70% identity to 1947–2008 ones. Third, over the past 60 years, 3 receptor-binding (RB) sites and 2 of the 8 glycosylation sites (amino acids 279 and 290) underwent considerable changes while the cleavage sites remained stable. Fourth, the human HA sequences differed completely from swine and avian isolates. Finally, the mutation of cleavage sites can change the three-dimensional structures, but single mutations cannot. Conclusions: Thus, in the past 60 years, Chinese H1N1 influenza HA genes kept stable with high affinity and low pathogenicity to human except changes in 2 glycosylation and 3 RB sites which were associated with the pandemic strength, range and host specificity of viruses.

Identification of a Dominant Epitope in the Hemagglutinin of an Asian Highly Pathogenic Avian Influenza H5N1 Clade 1 Virus by Selection of Escape Mutants

H5N1 avian influenza virus has caused widespread infection in poultry and wild birds, and has the potential to emerge as a pandemic threat to humans. The hemagglutinin (HA) is a glycoprotein on the surface of the virus envelope. Understanding its antigenic structure is essential for designing novel vaccines that can inhibit virus infection. The aim of this study was to map the amino acid substitutions that resulted in resistance to neutralization by monoclonal antibodies (MAbs) of the highly pathogenic A/crested eagle/Belgium/01/2004 (H5N1), a clade 1 virus. Two hybridomas specific to H5N1 clade 1 viruses were selected by enzyme-linked immunosorbent assay, virus neutralization test, and immunofluorescence assay. Escape mutant populations resisting neutralization by those MAbs (8C5 and 5A1) were then selected, and sequencing of these mutants allowed the prediction of the HA protein structure by molecular homology. We could detect an amino acid change in our escape mutants at position K189E corresponding to antigenic site 2 of H5 HA1 and site B of H3 HA1. Interestingly, 336 out of 350 available HA sequences from H5N1 clade 1 and clade 2.3 viruses had Lys (K) at position 189 in the HA1, whereas HA sequences analyzed from dade 2.1 and 2.2 viruses had Arg (R). This residue also interacts with the receptor-binding site, and it is thus important for the evolution of H5N1 viruses. An additional substitution K29E in HA2 subunit was also observed and identified with the use of NetChop software as a loss of a proteasomal cleavage site, which seems to be an advantage for H5N1 viruses.