Modulation of the pH Stability of Influenza Virus Hemagglutinin: A Host Cell Adaptation Strategy.
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 the respective mutations preserve their 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 life cycle and is dependent on endosomal 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 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 the 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 HA an excellent model of the way subtle structural modifications affect a protein's stability and enable it to function in diverse environments.
Institute of Biology, Humboldt Universität zu Berlin, Berlin, Germany; Departamento de Química Biológica e IQUIBICEN-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
Santiago
S
Di Lella
Institute of Biology, Humboldt Universität zu Berlin, Berlin, Germany.
Andreas
A
Herrmann
Institute of Biology, Humboldt Universität zu Berlin, Berlin, Germany. Electronic address: carolinemair001@gmail.com.
Caroline M
CM
Mair
D000220:Adaptation, Biological / Q000235:genetics / Q000502:physiology; D000818:Animals; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D053586:Virus Internalization
D019267:Hemagglutinin Glycoproteins, Influenza Virus