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

Santiago Manrique, Daniel Sauter, Florian A. Horenkamp, Sebastian Lülf, Hangxing Yu, Dominik Hotter, Kanchan Anand, Frank Kirchhoff and Matthias Geyer ()
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Santiago Manrique: University of Bonn
Daniel Sauter: Ulm University Medical Center
Florian A. Horenkamp: Department Physical Biochemistry
Sebastian Lülf: Department Physical Biochemistry
Hangxing Yu: Ulm University Medical Center
Dominik Hotter: Ulm University Medical Center
Kanchan Anand: University of Bonn
Frank Kirchhoff: Ulm University Medical Center
Matthias Geyer: University of Bonn

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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 Å 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.

Date: 2017
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DOI: 10.1038/s41467-017-00481-z

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