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(HN) Ectodomain Reveals a Four-Helix Bundle Stalk

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(HN) Ectodomain Reveals a Four-Helix Bundle Stalk Structure of the Newcastle disease virus hemagglutinin-neuraminidase (HN) ectodomain reveals a four-helix bundle stalk Ping Yuana, Kurt A. Swansonb,c,1, George P. Leserb,c,ReayG.Patersonc,RobertA.Lambb,c,2, and Theodore S. Jardetzkya,2 aDepartment of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and bHoward Hughes Medical Institute and cDepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208-3500 Contributed by Robert A. Lamb, July 20, 2011 (sent for review June 13, 2011) The paramyxovirus hemagglutinin-neuraminidase (HN) protein ment proteins are type II membrane proteins, with N-terminal plays multiple roles in viral entry and egress, including binding to transmembrane domains (TM) followed by a stalk region and sialic acid receptors, activating the fusion (F) protein to activate a C-terminal globular head domain (1). The hemagglutinin- membrane fusion and viral entry, and cleaving sialic acid from neuraminidase (HN) attachment proteins are thought to form carbohydrate chains. HN is an oligomeric integral membrane protein tetramers in their active form and are found in a subset of the fl consisting of an N-terminal transmembrane domain, a stalk region, paramyxoviruses, including parain uenza virus 5 (PIV5), mumps fl – and an enzymatically active neuraminidase (NA) domain. Structures virus, NDV, Sendai virus, and human parain uenza viruses 1 4. of the HN NA domains have been solved previously; however, the HN contributes multiple functions to the virus, including binding structure of the stalk region has remained elusive. The stalk region to receptor (sialic acid) for virus attachment to cells, receptor- contains specificity determinants for F interactions and activation, destroying (neuraminidase) activity for virus budding, and fusion protein activation. The C-terminal neuraminidase (NA) domain, underlying the requirement for homotypic F and HN interactions in obtained by proteolytic cleavage or expression of the NA domain viral entry. Mutations of the Newcastle disease virus HN stalk region alone, contains the receptor binding site and neuraminidase ac- have been shown to affect both F activation and NA activities, but tivity (4–6). a structural basis for understanding these dual affects on HN The F proteins form trimers and belong to the class I viral fusion MICROBIOLOGY functions has been lacking. Here, we report the structure of the protein group, which includes the influenza virus hemagglutinin, Newcastle disease virus HN ectodomain, revealing dimers of NA HIV gp160, and Ebola virus GP (1–3, 7–9). However, there is no domain dimers flanking the N-terminal stalk domain. The stalk sequence homology between class I fusion proteins, and they show forms a parallel tetrameric coiled-coil bundle (4HB) that allows only limited structural similarities, consisting of helical heptad classification of extensive mutational data, providing insight into repeat regions, HRA and HRB in F, and internal hydrophobic the functional roles of the stalk region. Mutations that affect both F fusion peptide sequences that are important in fusion. F initially activation and NA activities map predominantly to the 4HB hydro- folds to a metastable, prefusion conformation (1, 10). On activa- phobic core, whereas mutations that affect only F-protein activation tion, a dramatic refolding of the F protein is thought to catalyze the map primarily to the 4HB surface. Two of four NA domains interact membrane fusion process by juxtaposing the target cell membrane, with the 4HB stalk, and residues at this interface in both the stalk containing the inserted fusion peptides, with the viral membrane, and NA domain have been implicated in HN function. containing the C-terminal transmembrane domains at the end of HRB. The attachment glycoprotein is thought to activate F refolding, which requires proteins derived from the same para- he Paramyxoviridae are enveloped, negative-strand RNA myxovirus (1, 2, 11, 12). viruses that infect both humans and animals (1). The family is T The paramyxovirus HN protein stalk domain carries specificity divided into two major subfamilies, and it includes, among others, fl – determinants for F-protein activation, affects neuraminidase ac- mumps virus, measles virus, parain uenza viruses 1 5, Newcastle tivity, and contributes significantly to the oligomerization of the disease virus (NDV), Nipah virus, Hendra virus, respiratory syn- protein (1, 3, 12). Mutational studies of the NDV HN stalk have cytial virus, and metapneumovirus. Although successful vaccines examined effects on membrane fusion, NA activity, hemadsorp- have been developed for some of these pathogens, such as the – fi tion, F-protein complex formation, and oligomerization (13 16). measles and mumps viruses, it has proven more dif cult to de- Although mutations in the NDV HN stalk can affect both NA and velop successful therapeutics for others, particularly respiratory membrane fusion activities, it has not been clear how these two syncytial virus (RSV). RSV and human metapneumovirus (MPV) functions are coupled. Here, we report the crystal structure of the are second only to influenza virus in causing respiratory infections – fl intact NDV HN [Australia Victoria (AV) strain] ectodomain to and are followed by human parain uenza viruses (1). NDV in- ∼3.3 Å. The structure reveals a four-helix bundle (4HB) stalk fection of poultry has been responsible for imposing major eco- packed between two NDV NA domain dimers, which provide in- nomic costs. NDV, Nipah virus, and Hendra virus have been sight into the structural basis for stalk-dependent HN NA and fi classi ed in the United States as select agents. membrane fusion-promoting activities. The paramyxovirus RNA genome encodes 6–10 proteins, and virions contain two spike glycoproteins embedded in a lipid membrane that surrounds the matrix protein and nucleocapsid Author contributions: P.Y., K.A.S., G.P.L., R.G.P., R.A.L., and T.S.J. designed research; P.Y., core (1). For infections to proceed, the virion must fuse its lipid K.A.S., G.P.L., R.G.P., and T.S.J. performed research; P.Y. and K.A.S. contributed new envelope with a membrane of the host cell. For nearly all para- reagents/analytic tools; P.Y., K.A.S., G.P.L., R.G.P., R.A.L., and T.S.J. analyzed data; and myxoviruses, membrane fusion is triggered at the plasma mem- P.Y., K.A.S., G.P.L., R.G.P., R.A.L., and T.S.J. wrote the paper. brane in a receptor-dependent, pH-independent manner (1–3). The authors declare no conflict of interest. For most members of the virus family, the two viral glycoproteins Data deposition: The crystallography, atomic coordinates, and structure factors have been mediate this entry process—an attachment protein referred to as deposited in the Protein Data Bank, www.pdb.org (PDB ID code 3T1E). HN, H, or G, depending on the virus, and the fusion (F) glyco- 1Present address: Novartis Vaccines and Diagnostics, Cambridge, MA 02139. – protein (1 3). RSV and MPV do not require their attachment 2To whom correspondence may be addressed. E-mail: [email protected] or protein G for entry or to generate an infectious virus, indicating [email protected]. fi that the F proteins of these viruses are necessary and suf cient to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mediate cell penetration and infection (1). Most of the attach- 1073/pnas.1111691108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1111691108 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 Results and Discussion tion experiments and EM (Fig. 1 B and D). The NDV HN ecto- Soluble NDV HN Ectodomain Crystallizes as Tetramers and Reveals the domain, lacking the TM regions, forms a weaker tetramer than the Stalk 4HB. The NDV HN protein forms tetramers on the virion, corresponding PIV5 ectodomain, which exists as a homogeneous and similar to the PIV5 HN, the isolated head NA domains exist tetramer in solution (6, 17). fi primarily as monomers (4–6, 16–18). The HN stalk provides a For the NA domains that directly contact the stalk 4HB, the rst A significant driving force for oligomerization, but the TM domains observed residue is C123 (Fig. 2 ), whereas for the two NA fi are also thought to play a role (19). We expressed the NDV (AV) domains positioned above the stalk, the rst observed residue is HN ectodomain (stalk + head) (Fig. 1) and observed variable A125. The distances between the end of the stalk helices and each ∼ amounts of both monomers and dimers in gel filtration chroma- of the four NA domains range from 10 to 24 Å, with the longest tography separations (Fig. 1B), with a small number of potential distances across the observed twofold symmetric arrangement of tetramers evident in EM (Fig. 1D), which is consistent with the TM the four NA domains. The missing linker residues could span – domain stabilizing the tetramer (19). distances of 26 38 Å, ranging from 7 to 10 aa in an extended conformation, which is consistent with the distances observed The NDV HN ectodomain crystallized in space group P43212 and diffracted X-rays to 3.3 Å resolution (Table S1), and the between the individual helices and NA domain residues. Given the structure was solved by molecular replacement. Two copies of the twofold symmetry of the tetramer, preferential linkages between NA domains are located in the asymmetric unit, with the HN the two stalk helices most proximal to a pair of NA domain dimers tetramer lying along a crystallographic twofold axis (Fig. 2). seem most likely, because linkage distances are shorter and would Electron density maps showed the presence of a portion of the N- not lead to steric clashes at the top of the stalk 4HB. The distances terminal stalk region, forming a 4HB.
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