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==HIV-1 Nef in complex with the CD4 cytoplasmic domain and the AP2 clathrin adaptor complex==
<StructureSection load='6uri' size='340' side='right'caption='[[6uri]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6uri]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens], [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6URI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6URI FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6uri FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uri OCA], [https://pdbe.org/6uri PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uri RCSB], [https://www.ebi.ac.uk/pdbsum/6uri PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uri ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AP2A2_RAT AP2A2_RAT] Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha subunit binds polyphosphoinositide-containing lipids, positioning AP-2 on the membrane. The AP-2 alpha subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif (By similarity).<ref>PMID:14745134</ref> <ref>PMID:15473838</ref> 
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== Publication Abstract from PubMed ==
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-A 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.

Structural basis of CD4 downregulation by HIV-1 Nef.,Kwon Y, Kaake RM, Echeverria I, Suarez M, Karimian Shamsabadi M, Stoneham C, Ramirez PW, Kress J, Singh R, Sali A, Krogan N, Guatelli J, Jia X Nat Struct Mol Biol. 2020 Sep;27(9):822-828. doi: 10.1038/s41594-020-0463-z. Epub, 2020 Jul 27. PMID:32719457<ref>PMID:32719457</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6uri" style="background-color:#fffaf0;"></div>

==See Also==
*[[Adaptin 3D structures|Adaptin 3D structures]]
*[[Protein Nef 3D structures|Protein Nef 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Rattus norvegicus]]
[[Category: Jia X]]
[[Category: Kwon Y]]