Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 19, Issue 7, Pages 701-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2328
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Funding
- US National Institutes of Health (NIH) [AI097064, AI076040, AI038201]
- James B. Pendleton Charitable Trust
- California HIV-AIDS Research Program
- UCSD Center for AIDS Research (CFAR) [P30 AI36214]
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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 mu 1 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-mu 1 interface, which encompasses the cargo-recognition site of mu 1 and the proline-rich strand of Nef. The Nef C terminus induces a previously unobserved conformational change in mu 1, whereas the N terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on mu 1 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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