Crystal structure of reovirus attachment protein sigma1 reveals evolutionary relationship to adenovirus fiber - PubMed (original) (raw)

Comparative Study

Crystal structure of reovirus attachment protein sigma1 reveals evolutionary relationship to adenovirus fiber

James D Chappell et al. EMBO J. 2002.

Abstract

Reovirus attaches to cellular receptors with the sigma1 protein, a fiber-like molecule protruding from the 12 vertices of the icosahedral virion. The crystal structure of a receptor-binding fragment of sigma1 reveals an elongated trimer with two domains: a compact head with a new beta-barrel fold and a fibrous tail containing a triple beta-spiral. Numerous structural and functional similarities between reovirus sigma1 and the adenovirus fiber suggest an evolutionary link in the receptor-binding strategies of these two viruses. A prominent loop in the sigma1 head contains a cluster of residues that are conserved among reovirus serotypes and are likely to form a binding site for junction adhesion molecule, an integral tight junction protein that serves as a reovirus receptor. The fibrous tail is mainly responsible for sigma1 trimer formation, and it contains a highly flexible region that allows for significant movement between the base of the tail and the head. The architecture of the trimer interface and the observed flexibility indicate that sigma1 is a metastable structure poised to undergo conformational changes upon viral attachment and cell entry.

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Figures

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Fig. 1. Structure of reovirus σ1. (A) Ribbon drawing of the σ1 trimer. The three σ1 monomers are shown in red, orange and blue. Each monomer consists of a head domain formed by a compact β-barrel and a fibrous tail with three β-spiral repeats. Note the kink between the 3-fold axes of the head and tail domains. (B) Enlarged view of the σ1 head domain. The two Greek key motifs, shown in red and orange, form a compact, cylindrical β-sheet that contains eight β-strands (A–H). With the exception of the DE loop, the connections between the β-strands are very tight. The head domain also contains two short helices (blue): one 310 and one α-helix. (C) Schematic view of the β-strand arrangement in the σ1 head domain. Colors are as in (B); an additional D strand is shown in gray to depict the circular nature of the barrel. Strand D forms β-sheet-type hydrogen bonds with strands A and G.

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Fig. 2. Flexibility of σ1. (A) Superposition of the three σ1 monomers present in the crystals. The superposition is based on the N-terminal two β-spiral repeats and reveals flexibility in the linker region (residues 291–294) between repeats 2 and 3. (B) Superposition, as in (A), using σ1 trimers. This representation highlights the degree of flexibility within the σ1 trimer as it protrudes from the virion. Three σ1 trimers are shown in red, orange and blue.

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Fig. 3. Conservation of σ1 residues and predicted interaction with JAM. (A) Sequence alignment of T1L, T2J and T3D σ1. Conserved residues predicted to interact with JAM are shown in red; other conserved residues are shown in orange. (B) Surface representation of two σ1 monomers, with the third monomer shown as a blue ribbon. The conserved residues from (A) were mapped onto the σ1 surface using the same color code. The three views differ by rotations of 90° and 180°, respectively, along a vertical axis.

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Fig. 4. The σ1 head trimer interface. (A) View into the head trimer interface. Two monomers are shown as surface representations, and the third monomer is shown as a blue ribbon. Surface residues that are within 4 Å of residues in the third monomer are shown in red (residues conserved in T1L, T2J and T3D σ1) and yellow (residues unique to T3D σ1). The contact area involving conserved residues Val344, Asp345 and Asp346 is boxed, and this region is shown in more detail in (B). (B) View along the trimer axis, centered at conserved residues Asp345 and Asp346 (yellow) located at the base of the head. Residues Tyr313, Arg314 and Tyr347 engage in contacts with the two aspartic acids. The side chains of Asp345 are likely to be protonated to avoid an accumulation of negative charge at the interface. Hydrogen bonds involving protonated Asp345 are indicated. Oxygen and nitrogen atoms of side chains are shown as red and blue spheres, respectively, and the Asp346 main chain amides are shown as blue spheres as well.

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Fig. 5. Comparison of reovirus σ1 and adenovirus fiber structures. Trimeric structures of reovirus σ1 (A) and adenovirus fiber (B; van Raaij et al., 1999). In each case, one of the monomers is shown in red. Both attachment proteins have head-and-tail morphology, with a triple β-spiral forming the tail. The spirals of the crystallized reovirus σ1 fragment and adenovirus fiber (van Raaij et al., 1999) contain three and four repeats, respectively. (C) Superposition, in stereo, of σ1 head (red) and adenovirus fiber knob (blue; van Raaij et al., 1999). A portion of the β-spiral is shown in each case. The spirals emerge from the head domains in similar orientations and directions. In addition to the conserved β-sheet topology, the head and knob structures share a short helix (indicated in orange for σ1) in a long loop at the domain base.

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Fig. 5. Comparison of reovirus σ1 and adenovirus fiber structures. Trimeric structures of reovirus σ1 (A) and adenovirus fiber (B; van Raaij et al., 1999). In each case, one of the monomers is shown in red. Both attachment proteins have head-and-tail morphology, with a triple β-spiral forming the tail. The spirals of the crystallized reovirus σ1 fragment and adenovirus fiber (van Raaij et al., 1999) contain three and four repeats, respectively. (C) Superposition, in stereo, of σ1 head (red) and adenovirus fiber knob (blue; van Raaij et al., 1999). A portion of the β-spiral is shown in each case. The spirals emerge from the head domains in similar orientations and directions. In addition to the conserved β-sheet topology, the head and knob structures share a short helix (indicated in orange for σ1) in a long loop at the domain base.

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Fig. 6. Structure of the β-spiral repeats in the reovirus σ1 tail. (A) Detailed view of a section of the triple β-spiral of σ1. One σ1 chain is shown in orange; the other two are in gray. Residues Leu270, Met272, Ile274, Leu279 and Ile281 (blue) are located in β-strands and participate in the formation of a hydrophobic core that stabilizes the spiral. Residues Ser277 (blue) and Thr278 (magenta) are located in a β-turn that connects the two β-strands. The position of Thr278 is usually occupied by a proline or a glycine residue in β-spirals (van Raaij et al., 1999). (B) Sequence alignment of a region of the σ1 tail, indicating that the tail contains at least eight β-spiral repeats. The hydrophobic residues characteristic of β-spirals are indicated in blue, and the residues (usually proline or glycine) in the β-turns are shown in magenta. The consensus sequence for β-spiral repeats is shown at the bottom (h, hydrophobic residue; G, glycine; P, proline). Residues Asn198, Arg202 and Pro204 (shown in red) have been implicated in the interaction of T3D σ1 with sialic acid (Chappell et al., 1997). Arg245 (shown in blue) is the cleavage site for trypsin (Chappell et al., 1998). (C) Model of the complete spiral of σ1. Based on the sequence analysis shown in (B), the β-spiral probably begins at residue 167 of T3D σ1 and comprises eight repeats. The N-terminal five repeats are shown in gray. These repeats are not included in the crystal structure; the spiral has been extended using translated and rotated σ1 repeats to generate a model that depicts the approximate dimensions of the molecule. Residues prior to 167 are not shown; these residues are predicted to form an α-helical coiled-coil structure (Bassel-Duby et al., 1985; Duncan et al., 1990; Fraser et al., 1990; Nibert et al., 1990).

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