Modulation of the pH stability of influenza virus hemagglutinin - A host cell adaptation strategy

MAIR, CAROLINE; DI LELLA, SANTIAGO; HERRMANN, ANDREAS

BIOPHYSICAL JOURNAL

CELL PRESS

Lugar: United States; Año: 2016 vol. 110 p. 2293 - 2301

0006-3495

Proteins undergo dynamic structural changes to function within the range of physical and chemical conditions of their microenvironments. Changes in these environments affect their activity unless respective mutations preserve proper function. Here, we examine the influenza A virus spike protein, hemagglutinin (HA) which undergoes a dynamic conformational change that is essential to the viral lifecycle and is dependent on pH. Since the cells of different potential hosts exhibit different levels of pH, the virus can only cross species barriers if HA undergoes mutations that still permit the structural change to occur. This key event occurs after Influenza A enters the host cell via the endocytic route, during its intracellular transport inside endosomes. The acidic pH inside these vesicles triggers a major structural transition of HA that induces the fusion of the viral envelope and the endosomal membrane and permits the release of the viral genome. HA experiences specific mutations that alter its pH stability and allow the conformational changes required for fusion in different hosts, despite the differences in the degree of acidification of their endosomes. Experimental and theoretical studies over the past few years have provided detailed insights into the structural aspects of mutational changes that alter its susceptibility to different pH thresholds. We will illustrate how such mutations modify the protein´s structure and consequently its pH stability. These changes make hemagglutinin an excellent model of the way subtle structural modifications affect a protein´s stability and enable it to function in diverse environments.