한빛사 논문
Yonghwa Kwon1, Robyn M. Kaake2,3, Ignacia Echeverria4, Marissa Suarez5, Mohammad Karimian Shamsabadi1, Charlotte Stoneham5,6, Peter W. Ramirez6, Jacob Kress1, Rajendra Singh5,6, Andrej Sali4,7, Nevan Krogan2,3, John Guatelli5,6 and Xiaofei Jia1,*
1Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA, USA. 2Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. 3Gladstone Institutes, San Francisco, CA, USA. 4Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. 5The VA San Diego Healthcare System, San Diego, CA, USA. 6Department of Medicine, University of California, San Diego, La Jolla, CA, USA. 7Department of Pharmaceutical Chemistry and
Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA, USA.
*Corresponding author
Abstract
The HIV-1 Nef protein suppresses multiple immune surveillance mechanisms to promote viral pathogenesis and is an attractive target for the development of novel therapeutics. A key function of Nef is to remove the CD4 receptor from the cell surface by hijacking clathrin- and adaptor protein complex 2 (AP2)-dependent endocytosis. However, exactly how Nef does this has been elusive. Here, we describe the underlying mechanism as revealed by a 3.0-Å crystal structure of a fusion protein comprising Nef and the cytoplasmic domain of CD4 bound to the tetrameric AP2 complex. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. A pocket on Nef previously identified as crucial for recruiting class I MHC is also responsible for recruiting CD4, revealing a potential approach to inhibit two of Nef’s activities and sensitize the virus to immune clearance.
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