Structural Homology of the Central Conserved Region of the Attachment Protein G of Respiratory Syncytial Virus with the Fourth Subdomain of 55-kDa Tumor Necrosis Factor Receptor

Abstract

The attachment protein G of respiratory syncytial virus (RSV) has a modular architecture. The ectodomain of the protein comprises a small folded conserved region which is bounded by two mucin-like regions. In this study, a sequence and structural homology is described between this central conserved region of RSV-G and the fourth subdomain of the 55-kDa tumor necrosis factor receptor (TNFr). The three-dimensional structures of RSV-G and human TNFr were previously determined with NMR spectroscopy and X-ray crystallography, respectively. The C-terminal part of both subdomains fold into a cystine noose connected by two cystine bridges with the same spacing between cysteine residues and the same topology. Although a general structural similarity is observed, there are differences in secondary structure and other structural features. Molecular Dynamics calculations show that the BRSV-G NMR structure of the cystine noose is stable and that the TNFr crystal structure of the cystine noose drifts towards the BRSV-G NMR structure in the simulated solution environment. By homology modelling a model was built for the unresolved N-terminal part of the central conserved region of RSV-G. The functions for both protein domains are not known but the structural similarity of both protein domains suggests a similar function. Although the homology suggests that the cystine noose of RSV-G may interfere with the antiviral and apoptotic effect of TNF, the biological activity remains to be proven.

Antiviral Activity and Structural Characteristics of the Nonglycosylated Central Subdomain of Human Respiratory Syncytial Virus Attachment (G) Glycoprotein

“…attachment glycoprotein (48). Diminution of antiviral activity observed with truncations between residues 171 and 177 of G149 -177 and G154 -177 may have been due to steric occlusion of interactions necessary for antiviral activity.…”

“…A similarity in structure of the central subdomain of the BRSV attachment glycoprotein and the C-terminal module of the fourth subdomain of HTNFr has been proposed (48). These molecules have an identical cystine noose motif (i.e.…”

“…The structure of the cystine noose in the C-terminal portion of a synthetic form of the BRSV subdomain was determined by NMR (46); however, the N-terminal portion was not structured. A subsequent molecular dynamics simulation study (48) suggested a specific S-shaped loop structure for the N-terminal portion of the BRSV subdomain. This arrangement of an Sshaped N-terminal portion followed by a cystine noose is reminiscent of the structure of the fourth domain of the 55-kDa human tumor necrosis factor receptor (HTNFr) (48,49).…”

“…A cystine noose configuration was also indicated for BRSV by analyses of a synthetic peptide containing the bovine sequence with the four cysteine residues oxidized to form disulfides in vitro (45). Conformational detail has either been determined (46,47) or proposed (48) for the entire central subdomain of the BRSV attachment glycoprotein. The structure of the cystine noose in the C-terminal portion of a synthetic form of the BRSV subdomain was determined by NMR (46); however, the N-terminal portion was not structured.…”

The cysteine-rich region of respiratory syncytial virus attachment protein inhibits innate immunity elicited by the virus and endotoxin

“…The wide specificity of GCRR modulation suggests that its effects are exerted directly or indirectly through pathways common to a variety of proinflammatory agents. Interestingly, the conserved GCRR has a structural homology with the fourth subdomain of TNFR1, suggesting that its modulatory effect may be associated with binding and inactivation of TNF or an unknown TNF homologue (25). TNF also mediates endotoxin-induced shock, and TNFR1-deficient mice are resistant to lethal dosages of endotoxin (26,27).…”