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

Valerie E Pye,Peter Cherepanov,Giada Mattiuzzo,Yasuhiro Takeuchi,Robin Corey,Massimo Pizzato,Weston B Struwe,Idlir Liko,Allison Ballandras-Colas,Mark Hassall,Sarah L Maslen,Carol V Robinson,J Mark Skehel,Cinzia Bertelli,Phillip J Stansfeld,Annachiara Rosa,Andrea Nans

doi:10.1038/s41594-019-0357-0

Abstract

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.

Highlights

Each of the six identical DmSERINC subunits consists of ten transmembrane helices (TM) arranged into two subdomains revealing a tertiary fold that is ~35 Å by ~50 Å in the membrane plane and ~50 Å traversing the membrane (Fig. 1b)
When subjected to chromatography through a 24-ml Superdex-200 sizing column, SERINC5 migrated as a single peak with elution volume of 12 ml
Further studies will be required to test the functional significance of phosphatidylserine, sulfatide and/or cholesterol binding in biological functions of SERINC proteins

Summary

Introduction

Each of the six identical DmSERINC subunits consists of ten transmembrane helices (TM) arranged into two subdomains revealing a tertiary fold that is ~35 Å by ~50 Å in the membrane plane and ~50 Å traversing the membrane (Fig. 1b). A 39-residue-long α-helix (TM4) spans the membrane diagonally intersecting subdomain A (TM1, TM2, TM3, TM9) and subdomain B (TM5, TM6, TM7 and TM10). A shorter diagonal α-helix TM8 crosses back from subdomain B to A, forming an asymmetrical cross with TM4 in the centre. Two disulphide bonds are identified on the extracellular side: one within extracellular loop

Methods

Results

Conclusion