Structural Evolution of Trimeric Gamma-Type Retroviral Envelope Proteins

Abstract

The envelope glycoproteins (Env) of retroviruses are highly diverse due to their relatively rapid evolution and the ancient origin of retroviruses. Sequence similarity among the Env of retroviruses is observed in the transmembrane subunit (TM) of Env mediating membrane fusion, whereas this similarity is more limited or absent in the surface subunit (SU) mediating receptor binding. Recent structural modeling of the SU of major retroviral groups identified a structurally conserved {beta}-sheet domain in SU and the SU-equivalent of filoviruses, GP1, that is differentially expanded to generate the structural diversity observed in this protein family. Here, trimeric Env structures from three major exogenous and endogenous gamma-type retroviral Env classes were modeled with AlphaFold2 multimer to address the evolution of trimeric Env in the retroviruses. The models show a close structural relationship between the trimeric Env proteins of gammaretroviruses and alpharetroviruses and the trimeric filoviral spike protein, with an extended hydrophobic structure anchoring SU into TM in retroviral Env occluding the intersubunit disulfide bond. In addition, the murine leukemia virus (MLV) Env trimer model indicates that the type-C gammaretroviral receptor binding domains (RBD) are positioned on the side of the Env trimer pointing towards the viral envelope membrane, unlike those of the gammaretroviral RDR interference group, which are positioned closer to the apical end of the Env trimer. The trimeric MLV Env structural model, including RBD position, is consistent with previous trimeric MLV Env electron-density maps. The structural models provide insights into the structure, function and evolution of trimeric retroviral gamma-type Env.