Proteomics computational analyses suggest that the carboxyl terminal glycoproteins of Bunyaviruses are class II viral fusion protein (beta-penetrenes) - PubMed (original) (raw)

Proteomics computational analyses suggest that the carboxyl terminal glycoproteins of Bunyaviruses are class II viral fusion protein (beta-penetrenes)

Courtney E Garry et al. Theor Biol Med Model. 2004.

Abstract

The Bunyaviridae family of enveloped RNA viruses includes five genuses, orthobunyaviruses, hantaviruses, phleboviruses, nairoviruses and tospoviruses. It has not been determined which Bunyavirus protein mediates virion:cell membrane fusion. Class II viral fusion proteins (beta-penetrenes), encoded by members of the Alphaviridae and Flaviviridae, are comprised of three antiparallel beta sheet domains with an internal fusion peptide located at the end of domain II. Proteomics computational analyses indicate that the carboxyl terminal glycoprotein (Gc) encoded by Sandfly fever virus (SAN), a phlebovirus, has a significant amino acid sequence similarity with envelope protein 1 (E1), the class II fusion protein of Sindbis virus (SIN), an Alphavirus. Similar sequences and common structural/functional motifs, including domains with a high propensity to interface with bilayer membranes, are located collinearly in SAN Gc and SIN E1. Gc encoded by members of each Bunyavirus genus share several sequence and structural motifs. These results suggest that Gc of Bunyaviridae, and similar proteins of Tenuiviruses and a group of Caenorhabditis elegans retroviruses, are class II viral fusion proteins. Comparisons of divergent viral fusion proteins can reveal features essential for virion:cell fusion, and suggest drug and vaccine strategies.

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Figures

Figure 1

Colinear arrangement of similarities in Sindbis virus E1 and Sandfly fever virus Gc. Alignments were constructed as detailed in the text. Panel A: Linear arrangement of the domain structure of SIN E1 and proposed domain structure of SAN Gc according to the convention for class II viral fusion proteins (β-penetrenes) originally described for TBEV E by Rey et al. [5]. Regions of significant sequence similarities in SIN E1 and SAN Gc determined by the PRSS3 sequence alignment program are indicated. Probabilities (p values) are based on 1000 shuffles. Panel B: Amino acids are numbered from the beginning of the Sindbis virus subgenonic mRNA encoded polyprotein and the beginning of the SAN M segment encoded polyprotein. (:) refers to identical amino acids. (.) refers to chemically similar amino acids. Plum amino acids: N-glycosylation sites. Hydrophobic transmembrane domains were predicted using TMpred. Sequences with significant WWIHS scores were identified by MPeX (olive). In SAN Gc, predicted α-helices are indicated by dashed boxes and predicted β-sheets are underlined with a dashed arrow.

Figure 2

Model of Sandfly fever virus Gc based on predicted structure of a Sindbis virus E1 fusion intermediate. Panel A: A structural intermediate of SFV E1 as determined by Gibbons et al. [33] was projected to SIN E1. Panel B: A model fitting SAN GC to the predicted structure of SIN E1. Structures predicted to be similar are color-coded the same way in SIN E1 and SAN Gc. Grey lines: dicysteine linkages. Black stick figures: N-glycosylation sites (sites with central proline are often not used). Regions with significant Wimley-White interfacial hdrophobicity scale scores were predicted with MpeX (black).

Figure 3

Alignment of Gc amino acid sequences of prototype members of the five genuses of the Bunyaviridae family. Alignments were constructed by identifying the fusion peptide (red) and the transmembrane anchor (violet) as described in the text. Additional local sequence similarities were identified by using the Complign feature of MacMolly, the PRSS3 alignment algorithm or by inspection. Sequences with significant WWIHS scores (olive) were identified by MPeX.

Figure 4

Alignment of phlebovirus Gc amino acid sequences with Tenuivirus surface protein pvc2 and the carboxyl terminal Env protein of a Caenorhabditis elegans retrovirus. Sequences are color-coded as in Figure 3.

Figure 5

Common order of proteins in Bunyavirus M segment polyproteins. Related glycoproteins Gn and Gc are in the same order in the polyproteins of prototypic members of the Bunyaviridae. Prior designations of the glycoproteins are indicated in parentheses. Hydrophobic domains were predicted using TMpred. The O-glycosylation rich (mucin-like) region in CCHF was delineated using NetOGlyc 3.1 as described previously by Sanchez and coworkers [46]. These authors also described the indicated potential cleavages of the CCHF polyprotein.

Figure 6

Hypothetical model of Bunyavirus:cell fusion. Steps in the entry process of Bunyaviruses can be extrapolated from current models of class II viral fusion protein-mediated virion cell fusion. Panel A. The Bunyavirus glycoproteins Gn and Gc are modeled according to SIN virion structure analyses by Zhang et al. [31]. Based on limited similarities with Alphavirus E2 proteins (Table 3), Gn is depicted as the receptor-binding protein of Bunyaviruses. Certain Bunyaviruses may encode other membrane-associated proteins that interact with the fusion peptide or other regions of Gc. Panel B: Receptor-binding triggers uptake of Bunyavirus virion by endocytosis. Panel C: Acidification of the endocytic vesicle occurs via the action of proton transporters and may initiate Gn and Gc dissociation. Panel D: bending at the flexible "hinge" region beween domains I and II permits Gc trimer formation and insertion of the fusion peptide into the endosomal vesicle membrane. Panel D' Alternatively, Gc trimer formation may involve the rotation of domain III and a rearrangement (twist) of domain II as shown for SFV E1, DEN E and TBEV E [11,33,54]. Panel E: As previously proposed [11,33,54] the formation of more extensive Gc contacts in the trimers and stem regions may release of energy for distortion of the endosomal and viral membranes resulting in formation of "nipple-like" projections. Panel E': Alternatively, aa sequences of Gc that form a track with the ability to interface with bilayer membranes (Fig. 2, black), may facilitate mixing of the endosomal and viral membranes. Panel F: Formation of further trimer contacts and hemifusion. Hemifusion may not occur in the D' and E' pathway. Panel G: Formation of the "fusion pore" and entry of the ribonucleoprotein (RNP) segments. Modified from models and concepts proposed in references 9-12.

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Proteomics computational analyses suggest that the carboxyl terminal glycoproteins of Bunyaviruses are class II viral fusion protein (beta-penetrenes) - PubMed (original) (raw)