A bipartite structural organization defines the SERINC family of HIV-1 restriction factors.
Pye VE., Rosa A., Bertelli C., Struwe WB., Maslen SL., Corey R., Liko I., Hassall M., Mattiuzzo G., Ballandras-Colas A., Nans A., Takeuchi Y., Stansfeld PJ., Skehel JM., Robinson CV., Pizzato M., Cherepanov P.
The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity and sensitizes the virus to antibody-mediated neutralization. Here, using cryo-EM, we determine the structures of human SERINC5 and its orthologue from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively. The structures reveal a novel fold comprised of ten transmembrane helices organized into two subdomains and bisected by a long diagonal helix. A lipid binding groove and clusters of conserved residues highlight potential functional sites. A structure-based mutagenesis scan identified surface-exposed regions and the interface between the subdomains of SERINC5 as critical for HIV-1-restriction activity. The same regions are also important for viral sensitization to neutralizing antibodies, directly linking the antiviral activity of SERINC5 with remodeling of the HIV-1 envelope glycoprotein.