The Hemagglutinin-Neuraminidase (HN) Head Domain and the Fusion (F) Protein Stalk Domain of the Parainfluenza Viruses Affect the Specificity of the HN-F Interaction

Abstract

Membrane fusion by the parainfluenza viruses is induced by virus-specific functional interaction between the attachment protein (HN) and the fusion (F) protein. This interaction is thought to be mediated by transient contacts between particular amino acids in the HN stalk domain and those in the F head domain. However, we recently reported that replacement of specified amino acids at or around the dimer interface of the HN head domain remarkably affected the F protein specificity. We then intended to further investigate this issue in the present study and revealed that the HPIV2 HN protein can be converted to an SV41 HN-like protein by substituting at least nine amino acids in the HPIV2 HN head domain with the SV41 HN counterparts in addition to the replacement of the stalk domain, indicating that specified amino acids in the HN head domain play very important roles in determining the specificity of the HN-F interaction. On the other hand, we previously reported that the PIV5 F protein can be converted to an SV41 F-like protein by replacing 21 amino acids in the head domain of the PIV5 F protein with those of the SV41 F protein. We then intended to further investigate this issue in the present study and found that replacement of 15 amino acids in the stalk domain in addition to the replacement of the 21 amino acids in the head domain of the PIV5 F protein resulted in creation of a more SV41 F-like protein, indicating that specified amino acids in the F stalk domain play important roles in determining the specificity of the HN-F interaction. These results suggest that the conformations of the HN stalk domain and the F head domain are dependent on the structures of the HN head domain and the F stalk domain, respectively. Presumably, the conformations of the former domains, which are considered directly involved in the HN-F interaction, can be modified by subtle changes in the structure of the latter domains, resulting in an altered specificity for the interacting partners.

RETRACTED ARTICLE: Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and constructing more oncolytic viruses

“…Previous study showed that mutations at positions Asp198 and Arg174 reduced syncytial formation, suggesting that the HN gene plays a pivotal role in NDV-induced syncytial formation [ 21 ]. The interaction of HN and F proteins from the same viral strain is necessary for the most efficient function of receptor recognition and fusogenicity because the HN head domain carries the receptor-binding activities and the HN stalk domain harbors the site that determines the F protein specificity in promoting cell–cell fusion [ 22 , 23 ]. Furthermore, previous study suggested that F and HN cooperatively disturb mitochondrial fusion–fusion homeostasis to enhance mitochondrial biogenesis, synergistically inducing significant syncytia formation accompanied with complete autophagic flux in DF-1 and A549 cells [ 24 , 25 ].…”

Parainfluenza virus infections in patients with hematological malignancies or stem cell transplantation: Analysis of clinical characteristics, nosocomial transmission and viral shedding

“…Their major antigenic spike glycolproteins, hemagglutinin neuraminidase and fusion protein, are encoded by HN and F genes, respectively, and are dominant targets for humoral immunity found in all parainfluenza viruses [16]. Further, the HN protein comprises neuraminidase and hemagglutinin functions, and facilitates membrane fusion with host cells by interaction with the F protein [20,21].…”

Phylogenetic analysis of human parainfluenza type 3 virus strains responsible for the outbreak during the COVID-19 pandemic in Seoul, South Korea

“…The HN protein regulates virus-host interactions and has both hemagglutinin and neuraminidase activity (11). In addition, the HN protein affects the F protein's function in mediating membrane fusion with host cells (12). Because of its antigenicity and variability, the HN gene has been the preferred target gene region for the phylogenetic analysis of HPIV3 (13).…”