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Paramyxovirus Membrane Fusion: Lessons from the F and HN Atomic Structures

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Paramyxovirus Membrane Fusion: Lessons from the F and HN Atomic Structures View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Virology 344 (2006) 30 – 37 www.elsevier.com/locate/yviro Paramyxovirus membrane fusion: Lessons from the F and HN atomic structures Robert A. Lamb a,b,*, Reay G. Paterson b, Theodore S. Jardetzky b a Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208-3500, USA b Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3500, USA Received 30 August 2005; accepted 7 September 2005 Abstract Paramyxoviruses enter cells by fusion of their lipid envelope with the target cell plasma membrane. Fusion of the viral membrane with the plasma membrane allows entry of the viral genome into the cytoplasm. For paramyxoviruses, membrane fusion occurs at neutral pH, but the trigger mechanism that controls the viral entry machinery such that it occurs at the right time and in the right place remains to be elucidated. Two viral glycoproteins are key to the infection process—an attachment protein that varies among different paramyxoviruses and the fusion (F) protein, which is found in all paramyxoviruses. For many of the paramyxoviruses (parainfluenza viruses 1–5, mumps virus, Newcastle disease virus and others), the attachment protein is the hemagglutinin/neuraminidase (HN) protein. In the last 5 years, atomic structures of paramyxovirus F and HN proteins have been reported. The knowledge gained from these structures towards understanding the mechanism of viral membrane fusion is described. D 2005 Elsevier Inc. All rights reserved. Keywords: Viral fusion proteins; Attachment protein HN; Membrane fusion; Paramyxovirus; Fusion activation Contents Class I viral fusion proteins........................................................ 31 Core trimers of class I viral fusion proteins. ............................................... 31 Fusion triggering ............................................................. 31 Protein refolding and membrane fusion.................................................. 32 Paramyxovirus fusion: capture of intermediates of fusion ........................................ 32 A dual-functional F protein regulatory switch segment: activation and membrane fusion ........................ 32 A model for paramyxovirus-mediated fusion ............................................... 33 Atomic structure of the uncleaved ectodomain of the hPIV3 F protein.................................. 34 Atomic structure of HN and the role(s) of HN in fusion activation ................................... 35 Conclusions ................................................................ 36 Acknowledgments............................................................. 36 References ................................................................ 36 The paramyxoviruses are the etiological agents of many other animals and the Paramyxoviridae includes parainfluenza biologically and economically important diseases of man and virus 5 (PIV5) (formerly known as SV5), mumps virus, human parainfluenza virus type 2 (hPIV2) and type 4 (hPIV4), Sendai virus, hPIV1, hPIV3, Newcastle disease virus, measles virus, * Corresponding author. Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208- canine distemper virus, rinderpest virus, respiratory syncytial 3500, USA. Fax: +1 847 491 2467. (RS) virus and the newly emergent highly pathogenic Hendra E-mail address: [email protected] (R.A. Lamb). and Nipah viruses. Two viral glycoproteins are key to the 0042-6822/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.virol.2005.09.007 R.A. Lamb et al. / Virology 344 (2006) 30–37 31 infection process—an attachment protein that varies across viral families and the fusion (F) protein, which is found in all paramyxoviruses. For many of the paramyxoviruses (NDV, PIVs 1–5 and others), the attachment protein is the hemagglu- tinin/neuraminidase (HN) protein, but the morbilliviruses, such as measles virus, carry a hemagglutinin (H) protein in place of HN, while the pneumoviruses (RSV) and henipaviruses (Nipah and Hendra) express a distinct attachment glycoprotein (G). Class I viral fusion proteins Many viruses, such as influenza viruses, paramyxoviruses, human immunodeficiency virus, herpes viruses and dengue fever virus are enveloped in a lipid membrane and to replicate, these viruses must enter a cell by fusing their own membrane coat with that of the cell. Fusion is caused by viral glycoproteins that are inserted in the viral membrane. The paramyxovirus F proteins belong to the class I viral fusion protein type, of which the best characterized member is the influenza virus hemagglu- tinin (HA), but which also includes the fusion proteins from retroviruses, coronaviruses, Ebola virus and others (Colman and Lawrence, 2003; Dutch et al., 2000; Earp et al., 2005; Jardetzky and Lamb, 2004). Models for Class I viral fusion protein- mediated membrane merger have been developed primarily from the structural studies of HA (Skehel and Wiley, 2000). In Fig. 1. The paramyxovirus fusion protein and class I fusion protein core trimers. general, class I viral fusion proteins follow the following (A) Cleavage activation of a prototypical paramyxovirus F protein from paradigm. Three identical polypeptide chains assemble into parainfluenza virus 5 (PIV5). The position of the signal sequence, the TM domain, the cleavage site, the hydrophobic fusion peptide and the heptad trimers, which are subsequently proteolytically cleaved into two repeats A and B are indicated. 252 amino acid residues separate the two heptad fragments at a specific site N-terminal to an internal hydrophobic repeats. (B) Similar hairpin structures are formed by fragments of the domain of approximately 25 amino acids, commonly referred to membrane-anchored polypeptides of the fusion proteins from different viruses. as the fusion peptide (Fig. 1A). Sequences adjacent to the fusion (Modified from Baker et al., 1999.) peptide and the transmembrane (TM) anchor domain typically reveal a 4–3 (heptad) pattern of hydrophobic repeats and are temperatures near 100 -C. Intermediates along the pathway of designated HRA and HRB, respectively. membrane fusion can be trapped by the addition of peptides derived from either the N-terminal (HRA) or C-terminal (HRB) Core trimers of class I viral fusion proteins heptad repeat regions for many class I fusion proteins (Earp et al., 2005; Eckert and Kim, 2001; Fass, 2003), indicating that the Biophysical data indicated that HRA and HRB form a intact protein undergoes conformational changes that expose complex and crystallographic studies have shown that HRA and both HR regions, prior to refolding to the final 6HB. The HRB form a helical hairpin or 6-helix bundle structure (core intermediates are thought to represent partially refolded forms of trimer) that is related to that observed for the low-pH-induced the fusion protein, with a hydrophobic fusion peptide anchored proteolytic fragment of HA. For example, the core trimers of in the target cell membrane and the TM domains anchored to the PIV5 and hRSV F (Baker et al., 1999; Zhao et al., 2000), HIV viral membrane. The formation of the 6HB is tightly linked to the gp41 (Caffrey et al., 1998; Chan et al., 1997; Tan et al., 1997; merger of lipid bilayers, and is thought likely to couple the free Weissenhorn et al., 1997), Moloney murine leukemia virus energy released on protein refolding to membrane fusion envelope protein (Fass et al., 1996), Ebola GP2 (Malashkevich (Melikyan et al., 2000; Russell et al., 2001). et al., 1999; Weissenhorn et al., 1998) and HTLV-1 (Kobe et al., 1999) fusion proteins all share this similarity in structure (Fig. Fusion triggering 1B). While the structural details vary, all reveal a trimeric, coiled-coil beginning near the C-terminal end of the hydropho- The triggering event that initiates membrane fusion by bic fusion peptide. The C-terminal segment abutting the TM different viruses varies substantially for different viral fusion domain is also often helical and packs in an antiparallel direction proteins. For influenza virus, membrane fusion occurs upon along the outside of the N-terminal coiled-coil, placing the exposure to the low pH environment of the endosome (Bullough fusion peptides and TM anchors at the same end of a rod-like et al., 1994; reviewed in Hernandez et al., 1996), while HIVentry structure. These 6-helix bundles (6HB) typically represent a into cells is triggered by binding to the cell-surface proteins CD4 relatively small fraction of the intact fusion protein, yet their in conjunction with one of the chemokine receptor family structures are generally highly thermostable, with melting members (Damico et al., 1998; Furuta et al., 1998; Hernandez et 32 R.A. Lamb et al. / Virology 344 (2006) 30–37 al., 1997; Moore et al., 1990). For the paramyxoviruses, membrane fusion occurs at neutral pH, but the trigger mechanism for viral entry remains to be elucidated, although most likely it involves specific interactions with the attachment protein (HN, H or G) (reviewed in Lamb, 1993; Lamb and Kolakofsky, 2001). Protein refolding and membrane fusion The general mechanism for class I viral fusion proteins posits the folding of the uncleaved protein to a metastable state, which can be activated to undergo large conformational changes to a more stable fusogenic or post-fusion state. For the influenza
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