Abstract
Erns is an essential virion glycoprotein with RNase activity that suppresses host cellular innate immune responses upon being partially secreted from the infected cells. Its unusual C-terminus plays multiple roles, as the amphiphilic helix acts as a membrane anchor, as a signal peptidase cleavage site, and as a retention/secretion signal. We analyzed the structure and membrane binding properties of this sequence to gain a better understanding of the underlying mechanisms. CD spectroscopy in different setups, as well as Monte Carlo and molecular dynamics simulations confirmed the helical folding and showed that the helix is accommodated in the amphiphilic region of the lipid bilayer with a slight tilt rather than lying parallel to the surface. This model was confirmed by NMR analyses that also identified a central stretch of 15 residues within the helix that is fully shielded from the aqueous layer, which is C-terminally followed by a putative hairpin structure. These findings explain the strong membrane binding of the protein and provide clues to establishing the Erns membrane contact, processing and secretion.
Highlights
The genus Pestivirus belongs to the family Flaviviridae, together with the genera Hepacivirus, Flavivirus and Pegivirus
Erns is an essential structural component of the virus particle and an unspecific RNase. The latter activity is dispensable for pestivirus replication but represents a virulence factor involved in the establishment of lifelong persistent infection
These functions of Erns are connected with its repressive activity on the type I interferon response of the infected host probably depending on secretion of part of the protein synthesized within the infected cell followed by its distribution with the blood stream
Summary
The genus Pestivirus belongs to the family Flaviviridae, together with the genera Hepacivirus, Flavivirus and Pegivirus. Compared to the HCV RNA, the pestivirus genome codes for two additional proteins: the non-structural protein Npro, and the structural protein Erns [1] Both proteins interfere with the immune response of the infected animal and are important for establishing a persistent infection [4]. Erns consists of 227 amino acids, has a molecular weight of 42–48 kDa, being heavily glycosylated except for its C-terminal region [3,14,15] It is involved in the formation of infectious virus particles, but it is secreted from the infected cells, and up to 50 ng/ml of the protein can be detected in the blood of infected animals [16]. It could be shown that the deactivation of the RNase activity by deletion of one amino acid in the active site of the protein caused attenuation of the virus in its natural host [21,22]
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