Deep-Time Structural Evolution of Retroviral and Filoviral Surface Envelope Proteins

The retroviral surface envelope protein subunit (SU) mediates receptor binding and triggers membrane fusion by the transmembrane (TM) subunit. SU evolves rapidly under strong selective conditions, resulting in seemingly unrelated SU structures in highly divergent retroviruses. Structural modeling of the SUs of several retroviruses and related endogenous retroviral elements with AlphaFold 2 identifies a TM-proximal SU beta-sandwich structure that has been conserved in the orthoretroviruses for at least 110 million years. The SU of orthoretroviruses diversified by the differential expansion of the beta-sandwich core to form domains involved in virus-host interactions. The beta-sandwich domain is also conserved in the SU equivalent GP(1) of Ebola virus although with a significantly different orientation in the trimeric envelope protein structure relative to the beta-sandwich of human immunodeficiency virus type 1 gp120, with significant evidence for divergent rather than convergent evolution. The unified structural view of orthoretroviral SU and filoviral GP(1) identifies an ancient, structurally conserved, and evolvable domain underlying the structural diversity of orthoretroviral SU and filoviral GP(1). IMPORTANCE The structural relationships of SUs of retroviral groups are obscured by the high rate of sequence change of SU and the deep-time divergence of retroviral lineages. Previous data showed no structural or functional relationships between the SUs of type C gammaretroviruses and lentiviruses. A deeper understanding of structural relationships between the SUs of different retroviral lineages would allow the generalization of critical processes mediated by these proteins in host cell infection. Modeling of SUs with AlphaFold 2 reveals a conserved core domain underlying the structural diversity of orthoretroviral SUs. Definition of the conserved SU structural core allowed the identification of a homologue structure in the SU equivalent GP(1) of filoviruses that most likely shares an origin, unifying the SU of orthoretroviruses and GP(1) of filoviruses into a single protein family. These findings will allow an understanding of the structural basis for receptor-mediated membrane fusion mechanisms in a broad range of biomedically important retroviruses. The structural relationships of SUs of retroviral groups are obscured by the high rate of sequence change of SU and the deep-time divergence of retroviral lineages. Previous data showed no structural or functional relationships between the SUs of type C gammaretroviruses and lentiviruses.