Premature Activation of the Paramyxovirus Fusion Protein before Target Cell Attachment with Corruption of the Viral Fusion Machinery

Farzan, Shohreh F.; Palermo, Laura M.; Yokoyama, Christine C.; Orefice, Gianmarco; Fornabaio, Micaela; Sarkar, Aurijit; Kellogg, Glen E.; Greengard, Olga; Porotto, Matteo; Moscona, Anne

doi:10.1074/jbc.m111.256248

Cited by 37 publications

(68 citation statements)

References 58 publications

(58 reference statements)

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“…6 and 7), indicating that F has the ability to progress spontaneously. We also have found that, in the absence of HN, processed F is sensitive to proteolysis (18). Taken together, these data suggest that HN protects processed F from untimely activation (18,37), and only when it is receptor engaged does it proceed to activate F.…”

Section: Discussionsupporting

confidence: 49%

Spring-Loaded Model Revisited: Paramyxovirus Fusion Requires Engagement of a Receptor Binding Protein beyond Initial Triggering of the Fusion Protein

Porotto

DeVito

Palmer

et al. 2011

J Virol

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During paramyxovirus entry into a host cell, receptor engagement by a specialized binding protein triggers conformational changes in the adjacent fusion protein (F), leading to fusion between the viral and cell membranes. According to the existing paradigm of paramyxovirus membrane fusion, the initial activation of F by the receptor binding protein sets off a spring-loaded mechanism whereby the F protein progresses independently through the subsequent steps in the fusion process, ending in membrane merger. For human parainfluenza virus type 3 (HPIV3), the receptor binding protein (hemagglutinin-neuraminidase [HN]) has three functions: receptor binding, receptor cleaving, and activating F. We report that continuous receptor engagement by HN activates F to advance through the series of structural rearrangements required for fusion. In contrast to the prevailing model, the role of HN-receptor engagement in the fusion process is required beyond an initiating step, i.e., it is still required even after the insertion of the fusion peptide into the target cell membrane, enabling F to mediate membrane merger. We also report that for Nipah virus, whose receptor binding protein has no receptor-cleaving activity, the continuous stimulation of the F protein by a receptorengaged binding protein is key for fusion. We suggest a general model for paramyxovirus fusion activation in which receptor engagement plays an active role in F activation, and the continued engagement of the receptor binding protein is essential to F protein function until the onset of membrane merger. This model has broad implications for the mechanism of paramyxovirus fusion and for strategies to prevent viral entry.

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Section: Discussionsupporting

confidence: 49%

Spring-Loaded Model Revisited: Paramyxovirus Fusion Requires Engagement of a Receptor Binding Protein beyond Initial Triggering of the Fusion Protein

Porotto

DeVito

Palmer

et al. 2011

J Virol

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“…While the stalk domain is a major determinant for specific F activation, we propose that the globular head can be interchangeable and that the repressive role, if present, is due to the stalk domain. For HPIV3, HN not only specifically activates fusion after receptor engagement but also prevents premature activation of F before receptor engagement (57), and the stalk domain is responsible for the stabilization effect. The stability of the F protein in the absence of receptor protein may be different for each virus in the family and may be the product of adaptation of the viruses to specific hosts or tissues.…”

Section: Discussionmentioning

confidence: 99%

Measles Virus Fusion Machinery Activated by Sialic Acid Binding Globular Domain

Talekar

Moscona

Porotto

2013

J Virol

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“…However, the exact nature of these rearrangements and that of the F-HN/H/G interaction are not well understood. Multiple studies have shown that retargeted MeV H or NDV HN heads binding noncognate receptors are able to trigger F (45)(46)(47)(48)(49) and chimeric attachment proteins bearing globular heads or stalks from different viruses in various combinations are functional when paired with the cognate F protein corresponding to the stalk domain portion of the chimeric attachment protein (31,42,(49)(50)(51)(52)(53). Recent data have also shown that "headless" PIV5 HN, MeV H, and NiV G proteins, lacking the globular head domains in their entirety, are sufficient to trigger their cognate F proteins (42,54,55).…”

Section: Paramyxoviruses Are a Large Family Of Membrane-enveloped Negmentioning

confidence: 99%

Fusion Activation through Attachment Protein Stalk Domains Indicates a Conserved Core Mechanism of Paramyxovirus Entry into Cells

Bose

Song

Jardetzky

et al. 2014

J Virol

113

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Paramyxoviruses are a large family of membrane-enveloped negative-stranded RNA viruses causing important diseases in humans and animals. Two viral integral membrane glycoproteins (fusion [F] and attachment [HN, H, or G]) mediate a concerted process of host receptor recognition, followed by the fusion of viral and cellular membranes, resulting in viral nucleocapsid entry into the cytoplasm. However, the sequence of events that closely links the timing of receptor recognition by HN, H, or G and the "triggering" interaction of the attachment protein with F is unclear. F activation results in F undergoing a series of irreversible conformational rearrangements to bring about membrane merger and virus entry. By extensive study of properties of multiple paramyxovirus HN proteins, we show that key features of F activation, including the F-activating regions of HN proteins, flexibility within this F-activating region, and changes in globular head-stalk interactions are highly conserved. These results, together with functionally active "headless" mumps and Newcastle disease virus HN proteins, provide insights into the F-triggering process. Based on these data and very recently published data for morbillivirus H and henipavirus G proteins, we extend our recently proposed "stalk exposure model" to other paramyxoviruses and propose an "induced fit" hypothesis for F-HN/H/G interactions as conserved core mechanisms of paramyxovirus-mediated membrane fusion. HN, H, or G]) mediate a concerted process of host receptor recognition, followed by the fusion of viral and cellular membranes. We describe here the molecular mechanism by which HN activates the F protein such that virus-cell fusion is controlled and occurs at the right time and the right place. We extend our recently proposed "stalk exposure model" first proposed for parainfluenza virus 5 to other paramyxoviruses and propose an "induced fit" hypothesis for F-HN/H/G interactions as conserved core mechanisms of paramyxovirusmediated membrane fusion. IMPORTANCE Paramyxoviruses are a large family of membrane-enveloped negative-stranded RNA viruses causing important diseases in humans and animals. Two viral integral membrane glycoproteins (fusion [F] and attachment [

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Premature Activation of the Paramyxovirus Fusion Protein before Target Cell Attachment with Corruption of the Viral Fusion Machinery

Cited by 37 publications

References 58 publications

Spring-Loaded Model Revisited: Paramyxovirus Fusion Requires Engagement of a Receptor Binding Protein beyond Initial Triggering of the Fusion Protein

Spring-Loaded Model Revisited: Paramyxovirus Fusion Requires Engagement of a Receptor Binding Protein beyond Initial Triggering of the Fusion Protein

Measles Virus Fusion Machinery Activated by Sialic Acid Binding Globular Domain

Fusion Activation through Attachment Protein Stalk Domains Indicates a Conserved Core Mechanism of Paramyxovirus Entry into Cells

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