Interactions between AMOT PPxY motifs and NEDD4L WW domains function in HIV-1 release

J Biol Chem. 2021 Aug;297(2):100975. doi: 10.1016/j.jbc.2021.100975. Epub 2021 Jul 17.


Like most enveloped viruses, HIV must acquire a lipid membrane as it assembles and buds through the plasma membrane of infected cells to spread infection. Several sets of host cell machinery facilitate this process, including proteins of the endosomal sorting complexes required for transport pathway, which mediates the membrane fission reaction required to complete viral budding, as well as angiomotin (AMOT) and NEDD4L, which bind one another and promote virion membrane envelopment. AMOT and NEDD4L interact through the four NEDD4L WW domains and three different AMOT Pro-Pro-x (any amino acid)-Tyr (PPxY) motifs, but these interactions are not yet well defined. Here, we report that individual AMOT PPxY and NEDD4L WW domains interact with the following general affinity hierarchies: AMOT PPxY1>PPxY2>PPxY3 and NEDD4L WW3>WW2>WW1∼WW4. The unusually high-affinity of the AMOT PPxY1-NEDD4L WW3 interaction accounts for most of the AMOT-NEDD4L binding and is critical for stimulating HIV-1 release. Comparative structural, binding, and virological analyses reveal that complementary ionic and hydrophobic contacts on both sides of the WW-PPxY core interaction account for the unusually high affinity of the AMOT PPxY1-NEDD4L WW3 interaction. Taken together, our studies reveal how the first AMOT PPxY1 motif binds the third NEDD4L WW domain to stimulate HIV-1 viral envelopment and promote infectivity.

Keywords: AMOT; HIV; Nedd4L; PPxY; WW domains.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Angiomotins / metabolism*
  • Cell Line
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • HIV Infections / metabolism*
  • HIV Infections / pathology
  • HIV Infections / transmission
  • HIV Infections / virology
  • HIV-1 / isolation & purification
  • HIV-1 / metabolism*
  • HIV-1 / pathogenicity
  • Humans
  • Nedd4 Ubiquitin Protein Ligases / metabolism*
  • Protein Domains
  • Virus Assembly*


  • AMOT protein, human
  • Angiomotins
  • Endosomal Sorting Complexes Required for Transport
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4L protein, human