# HIV-1 Nef Uses a Conserved Pocket to Recruit the N-Terminal Cytoplasmic Tail of Serinc3

## TL;DR

This study reveals how HIV-1 Nef protein recruits Serinc3 to block its antiviral activity, offering insights into potential drug targets.

## Contribution

The study identifies a conserved Nef pocket involved in Serinc3 recruitment and links it to CD4 downregulation, suggesting a shared mechanism.

## Key findings

- Nef binds to the N-terminal cytosolic tail of Serinc3 to recruit it.
- Key Nef residues for Serinc3 binding overlap with those for CD4 downregulation.
- The conserved Nef pocket is a potential target for antiretroviral drugs.

## Abstract

Human transmembrane proteins Serinc3 and Serinc5 are antiviral restriction factors that inhibit HIV-1 infectivity. In the absence of viral antagonism, Serinc3 and Serinc5 incorporate into the envelopes of nascent virions and inhibit the fusion of virions to the target cells. The HIV-1 virus counteracts the restriction of Serinc3 by downregulating it from the cell surface and thus excluding it from budding virions. This is orchestrated by the viral accessory protein Nef and involves hijacking of the clathrin adaptor protein complex 2 (AP2)-dependent endocytosis. The mechanistic details of Nef-mediated Serinc3 downregulation, however, have been enigmatic. In this work, we investigated and revealed the molecular determinants of Serinc3 modulation by Nef. Our results show that Nef recruits Serinc3 by binding to its N-terminal cytosolic tail. Furthermore, Nef residues important for Serinc3-binding in vitro, and for the exclusion of Serinc3 from virions, overlap with those required for Nef-mediated CD4 downregulation, suggesting great mechanistic similarities between the two functions of Nef. In addition to shedding light on the mechanism of Serinc3 antagonism, our work also highlights the conserved substrate-binding pocket of Nef as a molecular hotspot for inhibitor development and antiretroviral drug discovery.