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Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef

Nature Structural & Molecular Biology volume 19, pages 701–706 (2012)Cite this article

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Abstract

The HIV-1 protein Nef inhibits antigen presentation by class I major histocompatibility complex (MHC-I). We determined the mechanism of this activity by solving the crystal structure of a protein complex comprising Nef, the MHC-I cytoplasmic domain (MHC-I CD) and the μ1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-μ1 interface, which encompasses the cargo-recognition site of μ1 and the proline-rich strand of Nef. The Nef C terminus induces a previously unobserved conformational change in μ1, whereas the N terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on μ1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity.

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Figure 1: Overall structure of Nef (cyan)–MHC-I CD (magenta)–μ1 (green) complex.
Figure 2: Nef compensates for an incomplete sorting motif in MHC-I.
Figure 3: Critical electrostatic interactions in the MHC-I CD–Nef–μ1 complex and a Nef-induced conformational change in μ1.
Figure 4: N-terminal helix of Nef positions the Nef core domain near the membrane for efficient interactions with MHC-I and μ1.
Figure 5: Distinct differences between μ1 and μ2 explain selective use of AP1 over AP2 by Nef for MHC-I downregulation.
Figure 6: Model of HIV-1 Nef-mediated association of MHC-I cytoplasmic domain with AP1 at lipid membrane.

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Acknowledgements

We thank Y. Modis and L. Wolfe for assistance in data collection. We also thank the staff at the Advanced Photon Source beamline 24-ID and the National Synchrotron Light Source beamline X29. This work was supported by US National Institutes of Health (NIH) grants AI097064 (Y.X.), AI076040 and AI038201 (J.G.) as well as by The James B. Pendleton Charitable Trust. R.S. was supported by grants from the California HIV-AIDS Research Program and the UCSD Center for AIDS Research (CFAR) developmental program P30 AI36214.

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Authors and Affiliations

  1. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA

    Xiaofei Jia, Haitao Yang & Yong Xiong

  2. Department of Medicine, University of California San Diego (UCSD), La Jolla, California, USA

    Rajendra Singh, Stefanie Homann & John Guatelli

  3. The VA San Diego Healthcare System, San Diego, California, USA

    Rajendra Singh, Stefanie Homann & John Guatelli

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  1. Xiaofei Jia
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  2. Rajendra Singh
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  3. Stefanie Homann
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  4. Haitao Yang
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X.J., J.G. and Y.X. designed the research; X.J., R.S., S.H., H.Y. and Y.X. performed the research; X.J., R.S., S.H., J.G. and Y.X. analyzed data; J.G. and Y.X. supervised the project; and X.J., J.G. and Y.X. wrote the manuscript.

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Correspondence to Yong Xiong.

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Jia, X., Singh, R., Homann, S. et al. Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef. Nat Struct Mol Biol 19, 701–706 (2012). https://doi.org/10.1038/nsmb.2328

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