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Endocytic sorting motif interactions involved in Nef-mediated downmodulation of CD4 and CD3

MPS-Authors

Manrique,  Santiago
Max Planck Institute of Molecular Physiology, Max Planck Society;
External Organizations;

Horenkamp,  Florian A.
Max Planck Institute of Molecular Physiology, Max Planck Society;

Luelf,  Sebastian
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;
Max Planck Institute of Molecular Physiology, Max Planck Society;

Anand,  Kanchan
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;
External Organizations;

Geyer,  Matthias
Research Group Physical Biochemistry, Center of Advanced European Studies and Research (caesar), Max Planck Society;
Max Planck Institute of Molecular Physiology, Max Planck Society;
External Organizations;

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Citation

Manrique, S., Sauter, D., Horenkamp, F. A., Luelf, S., Yu, H., Hotter, D., et al. (2017). Endocytic sorting motif interactions involved in Nef-mediated downmodulation of CD4 and CD3. Nature Communications, 8: 442. doi:10.1038/s41467-017-00481-z.


Cite as: http://hdl.handle.net/21.11116/0000-0001-78D6-7
Abstract
Lentiviral Nefs recruit assembly polypeptide complexes and target sorting motifs in cellular receptors to induce their internalization. While Nef-mediated CD4 downmodulation is conserved, the ability to internalize CD3 was lost in HIV-1 and its precursors. Although both functions play key roles in lentiviral replication and pathogenicity, the underlying structural requirements are poorly defined. Here, we determine the structure of SIVmac239 Nef bound to the ExxxLM motif of another Nef molecule at 2.5 angstrom resolution. This provides a basis for a structural model, where a hydrophobic crevice in simian immunodeficiency virus (SIV) Nef targets a dileucine motif in CD4 and a tyrosine-based motif in CD3. Introducing key residues into this crevice of HIV-1 Nef enables CD3 binding but an additional N-terminal tyrosine motif is required for internalization. Our resolution of the CD4/Nef/AP2 complex and generation of HIV-1 Nefs capable of CD3 downregulation provide insights into sorting motif interactions and target discrimination of Nef.