A bipartite structural organization defines the SERINC family of HIV-1 restriction factors

The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity and sensitises the virus to antibody-mediated neutralisation. Here, using cryo-electron microscopy, we determined the structures of human SERINC5 and its ortholog from Drosophila melanogaster at sub-nm and near-atomic resolution, respectively. The structures reveal a novel fold comprised of ten transmembrane helices organised 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 sensitisation to neutralising antibodies, directly linking the antiviral activity of SERINC5 with remodelling of the HIV-1 envelope glycoprotein.