Abstract:Measles virus (MV) entry requires at least 2 viral proteins, the hemagglutinin (H) and fusion (F) proteins. We describe the rescue and characterization of a measles virus with a specific mutation in the stalk region of H (I98A) that is able to bind normally to cells but infects at a lower rate than the wild type due to a reduction in fusion triggering. The mutant H protein binds to F more avidly than the parent H protein does, and the corresponding virus is more sensitive to inhibition by fusion-inhibitory pep… Show more
“…Though receptor engagement occurs through the globular head domains of the attachment proteins, an overwhelming amount of biochemical and biophysical evidence suggests that HN, H or G proteins physically interact with the F protein through these stalk domains. This interaction presumably triggers the F protein into carrying out its rearrangements leading to membrane fusion ( Bishop et al, 2007 , Bose et al, 2014 , Bose et al, 2011 , Bousse et al, 1994 , Corey and Iorio, 2007 , Deng et al, 1999 , Deng et al, 1995 , Ennis et al, 2010 , Melanson and Iorio, 2004 , Melanson and Iorio, 2006 , Paal et al, 2009 , Porotto et al, 2003 , Stone-Hulslander and Morrison, 1999 , Tanabayashi and Compans, 1996 ). Fig.…”
Section: Receptor Binding By the Attachment Proteins Initiates Activamentioning
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.
“…Though receptor engagement occurs through the globular head domains of the attachment proteins, an overwhelming amount of biochemical and biophysical evidence suggests that HN, H or G proteins physically interact with the F protein through these stalk domains. This interaction presumably triggers the F protein into carrying out its rearrangements leading to membrane fusion ( Bishop et al, 2007 , Bose et al, 2014 , Bose et al, 2011 , Bousse et al, 1994 , Corey and Iorio, 2007 , Deng et al, 1999 , Deng et al, 1995 , Ennis et al, 2010 , Melanson and Iorio, 2004 , Melanson and Iorio, 2006 , Paal et al, 2009 , Porotto et al, 2003 , Stone-Hulslander and Morrison, 1999 , Tanabayashi and Compans, 1996 ). Fig.…”
Section: Receptor Binding By the Attachment Proteins Initiates Activamentioning
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.
“…A substantial body of evidence including point mutations, additions of glycan moieties, chimeras, insertions, and truncations has established that residues in the stalk affect fusion promotion [21], [24], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36]. For NDV HN and several paramyxoviruses that utilize protein receptors, stalk mutations that block fusion have also been shown to disrupt coimmunoprecipitation with F [34], [27], [37], [36].…”
Paramyxoviruses cause a wide variety of human and animal diseases. They infect host cells using the coordinated action of two surface glycoproteins, the receptor binding protein (HN, H, or G) and the fusion protein (F). HN binds sialic acid on host cells (hemagglutinin activity) and hydrolyzes these receptors during viral egress (neuraminidase activity, NA). Additionally, receptor binding is thought to induce a conformational change in HN that subsequently triggers major refolding in homotypic F, resulting in fusion of virus and target cell membranes. HN is an oligomeric type II transmembrane protein with a short cytoplasmic domain and a large ectodomain comprising a long helical stalk and large globular head domain containing the enzymatic functions (NA domain). Extensive biochemical characterization has revealed that HN-stalk residues determine F specificity and activation. However, the F/HN interaction and the mechanisms whereby receptor binding regulates F activation are poorly defined. Recently, a structure of Newcastle disease virus (NDV) HN ectodomain revealed the heads (NA domains) in a “4-heads-down” conformation whereby two of the heads form a symmetrical interaction with two sides of the stalk. The interface includes stalk residues implicated in triggering F, and the heads sterically shield these residues from interaction with F (at least on two sides). Here we report the x-ray crystal structure of parainfluenza virus 5 (PIV5) HN ectodomain in a “2-heads-up/2-heads-down” conformation where two heads (covalent dimers) are in the “down position,” forming a similar interface as observed in the NDV HN ectodomain structure, and two heads are in an “up position.” The structure supports a model in which the heads of HN transition from down to up upon receptor binding thereby releasing steric constraints and facilitating the interaction between critical HN-stalk residues and F.
“…Biophysical studies have indicated that the stalk is tetrameric and predominantly helical in nature (50). The attachment protein of paramyxoviruses has been implicated in direct interaction with the fusion protein (4,5,12,13,27,34,44,45), and a variety of mutations in the stalk compromise fusion promotion (4,5,10,15,27,28,39,44). Interestingly, some of the stalk mutants, which are deficient for fusion, block the attachment protein-fusion protein interaction directly (as assessed by coimmunoprecipitation) (27,34,44).…”
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