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| Title: | Structural Basis of CD4 Downregulation by HIV-1 Nef |
| Authors: | Kwon, Yonghwa Kaake, Robyn Echeverria, Ignacia |
| Keywords: | AIDS;CD4 |
| Issue Date: | 2020 |
| Publisher: | Biochemical Journal |
| Abstract: | The HIV-1 protein Nef suppresses multiple immune surveillance mechanisms to promote viral pathogenesis1. Individuals infected with HIV-1 encoding defective nef genes do not develop AIDS for decades2,3. A key target of Nef is the cellular receptor CD4. Although essential for viral entry into host cells, CD4 is problematic for the virus later in its replication cycle: CD4 disrupts processing of the viral glycoprotein, Env, inhibiting infectivity4; it interferes with the release of new virions5,6; and it causes vulnerability to superinfection, causing premature cell death and limiting viral productivity7. Furthermore, binding of CD4 to Env exposes otherwise-concealed Env epitopes, rendering infected cells more susceptible to antibody-dependent cellular cytotoxicity and virus particles more susceptible to neutralizing antibodies8-10. HIV-1 has evolved strategies to mitigate these problems. Newly synthesized CD4 is targeted in the endoplasmic reticulum by the viral Vpu protein for proteasomal degradation11. Surface-expressed CD4, in contrast, is targeted by Nef for endocytosis and lysosomal degradation12-15. Nef’s effect on CD4 involves hijacking of clathrin adaptor complex 2 (AP2)-dependent endocytosis16,17. Although how Nef associates with a part of the tetrameric AP2 is understood18, a complete understanding of the interaction, especially how CD4 is sequestered by Nef into a complex with AP2, has remained elusive. Here, we present a high-resolution crystal structure that describes the underlying mechanism. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. Strikingly, 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 |
| Description: | Tài liệu này được phát hành theo giấy phép CC-BY-NC-ND 4.0 |
| URI: | http://dlib.m.m88hub.co/handle/HUST/24402 |
| Link item primary: | https://www.biorxiv.org/content/10.1101/2020.04.21.054007v1 |
| Appears in Collections: | OER - Kỹ thuật hóa học; Công nghệ sinh học - Thực phẩm; Công nghệ môi trường |
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