The viral transmembrane superfamily: possible divergence of Arenavirus and Filovirus glycoproteins from a common RNA virus ancestor

Abstract

Background: Recent studies of viral entry proteins from influenza, measles, human immunodeficiency virus, type 1 (HIV-1), and Ebola virus have shown, first with molecular modeling, and then X-ray crystallographic or other biophysical studies, that these disparate viruses share a coiled-coil type of entry protein.

Results: Structural models of the transmembrane glycoproteins (GP-2) of the Arenaviruses, lymphochoriomeningitis virus (LCMV) and Lassa fever virus, are presented, based on consistent structural propensities despite variation in the amino acid sequence. The principal features of the model, a hydrophobic amino terminus, and two antiparallel helices separated by a glycosylated, antigenic apex, are common to a number of otherwise disparate families of enveloped RNA viruses. Within the first amphipathic helix, demonstrable by circular dichroism of a peptide fragment, there is a highly conserved heptad repeat pattern proposed to mediate multimerization by coiled-coil interactions. The amino terminal 18 amino acids are 28% identical and 50% highly similar to the corresponding region of Ebola, a member of the Filovirus family. Within the second, charged helix just prior to membrane insertion there is also high similarity over the central 18 amino acids in corresponding regions of Lassa and Ebola, which may be further related to the similar region of HIV-1 defining a potent antiviral peptide analogue.

Conclusions: These findings indicate a common pattern of structure and function among viral transmembrane fusion proteins from a number of virus families. Such a pattern may define a viral transmembrane superfamily that evolved from a common precursor eons ago.

Figure 1

Models of the Transmembrane Proteins GP-2 of Lassa Virus and LCMV. Projections of the model structure for GP-2 of Lassa and LCMV are shown in parallel with one another, based on the consensus structures for algorithms of both viral amino acid sequences. Proposed helices are shown in helical net projection with sequential amino acids connected by solid lines. Proposed disulfide linkages are indicated by double lines. Hydrophobic amino acids are grouped with a solid background; neutral amino acids with a heavily outlined circle; hydrophilic amino acids with a light circle; glycosylation sites indicated by tridents. A heavy solid line indicates the point of proteolytic cleavage of the GP-C precursor protein to yield GP-1 and GP-2. Cysteines are highlighted by larger red circles. The surface membrane of the virus is indicated by a solid purple rectangle, the amino-terminal hydrophobic region by a yellow rectangle, and the conserved B-cell epitope by a blue rectangle. The two proposed antiparallel helices are labeled "AmphiHelix" for the extended heptad repeat, and "CPI Helix" for the charged, pre-insertion helix.

Figure 2

Concentric Helical Wheel Projections of Proposed Lassa and Ebola Helices. Helical wheel projections are shown for 18 amino acid segments of the proposed helices of Lassa and Ebola viruses. The projections are arranged concentrically to align the viral sequences, with the inner sequence that from Lassa virus, and the outer sequence from Ebola. Zaire virus (Genbank U31033). Rectangles indicate identical or highly similar residues in each sequence. Heavy lines indicate the hemicylinder of charge exclusion (hydrophobic) subtending an angle of 160° in each alignment. Below each wheel projection the linear sequences are also aligned to show the identities (solid lines) and high similarities (dotted lines). A. Concentric alignment of the amino terminal amphipathic helices ("lower amphi") of Lassa (amino acids 309-326, in wheel positions 1-18 respectively) and Ebola (555-572). B. Concentric alignment of the charged, pre-insertion helices ("CPI Helix") of Lassa (398-415) and Ebola (618-635).