PT  - JOURNAL ARTICLE
AU  - Cosmo Z. Buffalo
AU  - Christina M. Stürzel
AU  - Elena Heusinger
AU  - Dorota Kmiec
AU  - Frank Kirchhoff
AU  - James H. Hurley
AU  - Xuefeng Ren
TI  - Structural basis for tetherin antagonism as a barrier to zoonotic lentiviral transmission
AID  - 10.1101/638890
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 638890
4099  - http://biorxiv.org/content/early/2019/05/17/638890.short
4100  - http://biorxiv.org/content/early/2019/05/17/638890.full
AB  - Tetherin is a host defense that physically prevents escape of virions from the plasma membrane. Human tetherin lacks the motif DIWK antagonized by SIV, the antecedent of HIV. Here, we reconstituted the AP-2 clathrin adaptor complex with a simian tetherin and SIV Nef and determined its structure by cryo-EM. Nef refolds the first α-helix of the β2 subunit of AP-2 to a β hairpin, creating a binding site for the DIWK sequence. The tetherin binding site in Nef is distinct from those of MHC-I, CD3, and CD4, but overlaps the site for SERINC5 restricting viral infectivity. The structure explains the dependence of SIVs on the host tetherin DIWK sequence and the consequent barrier to human transmission.