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.


 

References:

Beitari, S., Q. Pan, A. Finzi, and C. Liang. (2020). Differential pressures of SERINC5 and IFITM3 on HIV-1 envelope glycoprotein over the course of HIV-1 infection. J. Virol. [Epub: Ahead of Print]
Krapp, S., E. Greiner, B. Amin, U. Sonnewald, and B. Krenz. (2017). The stress granule component G3BP is a novel interaction partner for the nuclear shuttle proteins of the nanovirus pea necrotic yellow dwarf virus and geminivirus abutilon mosaic virus. Virus Res 227: 6-14.
Okuda, K., S. Yanagihara, T. Sugayama, T. Zendo, J. Nakayama, and K. Sonomoto. (2010). Functional significance of the E loop, a novel motif conserved in the lantibiotic immunity ATP-binding cassette transport systems. J. Bacteriol. 192: 2801-2808.
Pye, V.E., A. Rosa, C. Bertelli, W.B. Struwe, S.L. Maslen, R. Corey, I. Liko, M. Hassall, G. Mattiuzzo, A. Ballandras-Colas, A. Nans, Y. Takeuchi, P.J. Stansfeld, J.M. Skehel, C.V. Robinson, M. Pizzato, and P. Cherepanov. (2020). A bipartite structural organization defines the SERINC family of HIV-1 restriction factors. Nat Struct Mol Biol 27: 78-83.
Usami, Y., Y. Wu, and H.G. Göttlinger. (2015). SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef. Nature 526: 218-223.
Examples:

TC#NameOrganismal TypeExample
9.A.29.1.1

LanG is a Lantibiotic immunity protein. It may or may not function with LanEF (an ABC antibiotic exporter; TC 3.A.1.131.2) (Okuda et al., 2010). The 6 TMSs of LanG show sequence similarity with TMSs 6-10 of DME family proteins (see 2.A.7.3.17).

 

Bacteria

LanG of Bacillus licheniformis (A5A639)

 
Examples:

TC#NameOrganismal TypeExample
9.A.29.2.1

Uncharacterized protein of 445 aas and 11 TMSs

Bacteroidetes

UP of Bacteroides sp.

 
9.A.29.2.2

Uncharacterized protein of 393 aas and 7 - 9 TMSs.

UP of Acidobacteria bacterium (soil metagenome)

 
9.A.29.2.3

Uncharacterized protein of 486 aas and 9 TMSs.

UP of a bacterium

 
9.A.29.2.4

Uncharacterized protein of 427 aas and 9 or 10 TMSs in a 5 or 6 + 3 TMS arrangement.

UP of Candidatus Woesearchaeota archaeon (groundwater metagenome)

 
Examples:

TC#NameOrganismal TypeExample
9.A.29.3.1

Uncharacterized protein of 441 aas and 11 TMSs.

UP of Schizosaccharomyces pombe (Fission yeast)

 
9.A.29.3.2

Uncharacterized NTF2 domain-containing protein of 528 aas and 8 TMSs in a 6 + 2 arrangement (Krapp et al. 2017).

UP of Arabidopsis thaliana (Mouse-ear cress)

 
9.A.29.3.3

Serine incorporator 5, SERINC5, of 708 aas and 7 - 10 TMSs.

SERINC5 of Clonorchis sinensis (Chinese liver fluke)

 
9.A.29.3.4

Serine incorporator 3 of 473 aas and 11 TMSs. May exhibit L-serine transmembrane transport activity.  Restriction factor required to restrict infectivity of lentiviruses, such as HIV-1: acts by inhibiting an early step of viral infection. Impairs the penetration of the viral particle into the cytoplasm (Usami et al. 2015).

Serinc3 of Homo sapiens

 
9.A.29.3.5

Serine incorporator 5, SERINC5, of 423 aas and 10 or 11 TMSs.  The 3-D structure has been determined (Pye et al. 2020). See paragraph 2 in the family description for details. SERINC5 and IFITM3 block fusioin of HIV-1 envelope glycoprotein with the cell membrane during the course of HIV-1, but at different stages of viral infection (Beitari et al. 2020).

 

SERINC5 of Homo sapiens