Structural Rearrangements of the Central Region of the Morbillivirus Attachment Protein Stalk Domain Trigger F Protein Refolding for Membrane Fusion

Ader, Nadine; Brindley, Melinda A.; Avila, Mislay; Origgi, Francesco C.; Langedijk, Johannes P. M.; Örvell, Claes; Vandevelde, M.; Zurbriggen, Andreas; Plemper, Richard K.; Plattet, Philippe

doi:10.1074/jbc.m112.342493

Cited by 65 publications

(125 citation statements)

References 46 publications

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“…The similarity of NDV and PIV5 HN stalk F-activating regions are such that maintaining the relative positions of critical hydrophobic residues in the context of the 4HB is sufficient to activate NDV F by a chimeric NDV HN protein containing part of the PIV5 HN F-activating region. In addition, we show a requirement for stalk flexibility at the F activation region of NDV HN similar to that observed for MeV and CDV H proteins (43,44,56). Lastly, we show that like PIV5 HN, MeV H, and NiV G, "headless" stalk domains of MuV HN and NDV HN, can trigger F and cause cellcell fusion.…”

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

confidence: 78%

“…F, on interaction with this region, is triggered (destabilized), ultimately resulting in membrane fusion (41,42). Current modeling and mutagenesis data suggest that F-activating regions are at or around the junction of the linear and superhelical regions of 4HB stalks (29,41,43,44). Very recently, Brindley et al (54) and Liu et al (55), for MeV and NiV, respectively, provided strong evidence that the "stalk exposure" model could be extrapolated to MeV and NiV.…”

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

confidence: 99%

“…The attachment protein globular heads upon binding receptor are thought to initiate a conformational change or rearrangement within the HN, H, or G proteins that is believed to be responsible for F activation during or after F-HN/H/G interaction (1,(42)(43)(44)(45). However, the exact nature of these rearrangements and that of the F-HN/H/G interaction are not well understood.…”

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

confidence: 99%

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

confidence: 78%

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

confidence: 99%

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

confidence: 99%

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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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“…This movement exposes critical residues in the stalk domain that interact with and trigger F to initiate membrane fusion (41,62,63). This model is based on the following observations: (i) mutations in HN that affect only fusion activity map to the stalk region of the attachment protein of several paramyxoviruses (12,18,42,43,64,65); (ii) headless PIV5 and NDV HN, MeV H, and NiV G are sufficient to trigger fusion (41,63,66,67); (iii) the head domains of HN have been observed by EM to be in various orientations relative to the stalk for NDV (12) and PIV5 (41); (iv) a crystal structure of the tetrameric NDV HN ectodomain reveals the heads in the down position, forming an interface with the stalk that overlaps with the critical fusion (69) was used to morph high-resolution structures of HN, F, and the humanized anti-HER2 Fab, 4D5 (which the sAb phage library was based on), to 15-Å surface representations. Protein Data Bank (PDB) entries 3T1E and 3TSI were overlaid and used for the HN four-heads-down model.…”

Section: Figmentioning

confidence: 99%

“…Upon binding receptor, the attachment protein globular heads are thought to initiate a rearrangement, and this movement is believed to be responsible for F activation during the F-HN/H/G interaction (1,(41)(42)(43)(44).…”

mentioning

confidence: 99%

Probing the Functions of the Paramyxovirus Glycoproteins F and HN with a Panel of Synthetic Antibodies

Welch

Paduch

Leser

et al. 2014

J Virol

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Paramyxovirus Entry

Bossart

Fusco²,

Broder³

2013

Advances in Experimental Medicine and Biology

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The family Paramyxoviridae consists of a group of large, enveloped, negative-sense, single-stranded RNA viruses and contains many important human and animal pathogens. Molecular and biochemical characterization over the past decade has revealed an extraordinary breadth of biological diversity among this family of viruses. Like all enveloped viruses, paramyxoviruses must fuse their membrane with that of a receptive host cell as a prerequisite for viral entry and infection. Unlike most other enveloped viruses, the vast majority of paramyxoviruses contain two distinct membrane-anchored glycoproteins to mediate the attachment, membrane fusion and particle entry stages of host cell infection. The attachment glycoprotein is required for virion attachment and the fusion glycoprotein is directly involved in facilitating the merger of the viral and host cell membranes. Here we detail important functional, biochemical and structural features of the attachment and fusion glycoproteins from a variety of family members. Specifically, the three different classes of attachment glycoproteins are discussed, including receptor binding preference, their overall structure and fusion promotion activities. Recently solved atomic structures of certain attachment glycoproteins are summarized, and how they relate to both receptor binding and fusion mechanisms are described. For the fusion glycoprotein, specific structural domains and their proposed role in mediating membrane merger are illustrated, highlighting the important features of protease cleavage and associated tropism and virulence. The crystal structure solutions of both an uncleaved and a cleavage-activated metastable F are also described with emphasis on how small conformational changes can provide the necessary energy to mediate membrane fusion. Finally, the different proposed fusion models are reviewed, featuring recent experimental findings that speculate how the attachment and fusion glycoproteins work in concert to mediate virus entry.

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Structural Rearrangements of the Central Region of the Morbillivirus Attachment Protein Stalk Domain Trigger F Protein Refolding for Membrane Fusion

Cited by 65 publications

References 46 publications

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

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

Probing the Functions of the Paramyxovirus Glycoproteins F and HN with a Panel of Synthetic Antibodies

Paramyxovirus Entry

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