9.A.29 The Lantibiotic Immunity Protein/Serine Connector Protein (LIP/SIP) Family
LanG may or may not function with LanEF ( an ABC antibiotic exporter; TC 3.A.1.131.2) (Okuda et al., 2010).
HIV-1 Nef and the unrelated mouse leukaemia virus glycosylated Gag (glycoGag) proteins strongly enhance the infectivity of HIV-1 virions produced in certain cell types in a clathrin-dependent manner. Usami et al. 2015 showed that Nef and glycoGag prevent the incorporation of the multipass transmembrane proteins serine incorporator 3 (SERINC3; TC# 9.A.29.3.4) and SERINC5 into HIV-1 virions to an extent that correlates with infectivity enhancement. Silencing of both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. The infectivity of nef-deficient virions increased more than 100-fold when produced in double-knockout human CD4+ T cells that lacked both SERINC3 and SERINC5, and re-expression experiments confirmed that the absence of SERINC3 and SERINC5 accounted for the infectivity enhancement. Furthermore, SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. SERINC3 and SERINC5 are highly expressed in primary human HIV-1 target cells, and inhibiting their downregulation by Nef is a potential strategy to combat HIV/AIDS (Usami et al. 2015).
As noted above, SERINC5 potently restricts HIV-1 infectivity and sensitizes the virus to antibody-mediated neutralization. Using cryo-EM, Pye et al. 2020 determined the structures of human SERINC5 and its orthologue from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively. The structures revealed 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 highlighted 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 important for viral sensitization to neutralizing antibodies, directly linking the antiviral activity of SERINC5 with remodeling of the HIV-1 envelope glycoprotein (Pye et al. 2020).
The family appears to show significant sequence similarity to the O-antigen polymerase superfamily which includes families 9.B.67 and 9.B.128.