Fusion activation by a headless parainfluenza virus 5 hemagglutinin- neuraminidase stalk suggests a modular mechanism for triggering

Department of Molecular Biosciences and Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2012; 109(39):E2625-34. DOI: 10.1073/pnas.1213813109
Source: PubMed


The Paramyxoviridae family of enveloped viruses enters cells through the concerted action of two viral glycoproteins. The receptor-binding protein, hemagglutinin-neuraminidase (HN), H, or G, binds its cellular receptor and activates the fusion protein, F, which, through an extensive refolding event, brings viral and cellular membranes together, mediating virus-cell fusion. However, the underlying mechanism of F activation on receptor engagement remains unclear. Current hypotheses propose conformational changes in HN, H, or G propagating from the receptor-binding site in the HN, H, or G globular head to the F-interacting stalk region. We provide evidence that the receptor-binding globular head domain of the paramyxovirus parainfluenza virus 5 HN protein is entirely dispensable for F activation. Considering together the crystal structures of HN from different paramyxoviruses, varying energy requirements for fusion activation, F activation involving the parainfluenza virus 5 HN stalk domain, and properties of a chimeric paramyxovirus HN protein, we propose a simple model for the activation of paramyxovirus fusion.

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    • "This, and the various observed MeV globular head arrangements in the atomic structure (Hashiguchi et al., 2011) suggest that the extent of F accessibility to the stalk in the '4 heads down'-like conformation may vary significantly for morbillivirus H proteins. Though the exact details of how morbillivirus F–H complexes initially prevent premature F activation require to be worked out in detail, biochemical and modeling studies of morbilliviruses (Brindley et al., 2015; Navaratnarajah et al., 2014, 2012) suggest that the core paramyxovirus fusion mechanism is conserved according to the 'stalk exposure' model, where the HN, H or G head domains act as regulators and the stalks act as activating domains (Bose et al., 2012). Liu and colleagues recently proposed a 3-step process of Henipavirus F activation, which suggests that, a bidentate G–F interaction of the F protein head with the G protein upper stalk or head prevents F from interacting with the G stalk F-activating region prematurely (Liu et al., 2013). "
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    ABSTRACT: The Paramyxoviridae include some of the great and ubiquitous disease-causing viruses of humans and animals. In most paramyxoviruses, two viral membrane glycoproteins, fusion protein (F) and receptor binding protein (HN, H or G) mediate a concerted process of recognition of host cell surface molecules followed by fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. The interactions between the F and HN, H or G viral glycoproteins and host molecules are critical in determining host range, virulence and spread of these viruses. Recently, atomic structures, together with biochemical and biophysical studies, have provided major insights into how these two viral glycoproteins successfully interact with host receptors on cellular membranes and initiate the membrane fusion process to gain entry into cells. These studies highlight the conserved core mechanisms of paramyxovirus entry that provide the fundamental basis for rational anti-viral drug design and vaccine development. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "This back-folded organization may preclude productive lateral interaction with prefusion F trimers. Consequently, Yuan and colleagues speculated that upon receptor binding, the two dimers move into a “heads-up” position, which uncovers the F interaction sites in the HN stalk region and facilitates HN/F interactions (51). Consistent with this model, HN-type paramyxovirus attachment proteins are thought not to interact with F trimers in the secretory system of the host cell and typically do not coprecipitate with F (52). "
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