Arden , et al. A molecular replacement solution was found using partial structures derived from the locked AP-2 core PDB: AP-2 complex at the molecular level and identified the amino acid residues within the Nef protein that interact with the AP-2 protein. Boehm unnamed coding system. Nef complex Jia et al. Conformation of the dileucine-based sorting motif in HIV-1 Nef revealed by intermolecular domain assembly.
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The intramolecular interactions of H4 are with other sections of the central loop, explaining why this helix has not been observed in other structures of Nef.
Although not essential for infection in cell culture, Nef enhances viral replication and disease progression in vivo. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients.
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Its key role appears to be to anchor the turn section to the N-terminus of helix H3. Asp is partially buried in a contact with the Nef core, and forms a salt bridge with Arg Fluorescence-activated cell sorting analysis FACS analysis was performed as described before Chaudhuri et al.
That would make the information more accessible, and also allow the authors to remove detailed descriptions of interfaces and contacts from the text. A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex.
NSMB 19, Consequently, the authors should consider whether analyzing the effects of mutating R of Nef in the yeast three hybrid and CD4 downregulation assays would make a more complete story. Hui at Iverson Software. Host proteins, unlike viral proteins, are not susceptible to rapid mutation nor are they under selective pressure to resist therapy. Moler at the University of New Mexico. Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef.
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Author information Article notes Copyright and License information Disclaimer. E The key Nef diacidic motif Asp and Asp forms intramolecular hydrogen bonds that stabilize the loop conformation. A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex. Although it is tempting to hypothesize that these basic residues interact with the Nef diacidic motif, there is currently no direct evidence for such an interaction.
Several aspects of the work are of particular interest and importance, including:. However, concerns about the development of drug resistance in addition to their side effects have fueled a continued search for additional targets. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. Kildall at Digital Research. The affinity and kinetics of CD4 binding to the AP Combination therapies with these agents have dramatically reduced HIV-1 transmission as well as HIVassociated morbidity and mortality.
The search for ways to combat the emergence of resistance to antiretrovirals, and to ultimately eradicate HIV, has led to an intense interest in targeting the interactions of HIV and host proteins Jaeger et al.
Horninget al. A The unlocked conformation of AP-2 core bound to myristoylated Nef orange. This suggests that multivalent interactions between Nef, CD4, and AP-2 likely drive cooperativity in the formation of the ternary complex.
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Mutations in the regions of AP-2 that were already known to bind dileucine signals had the expected loss of interaction. Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4.
National Center for Biotechnology InformationU. Mutation of Nef R to Ala was already shown to impair binding to alpha-sigma2 in the yeast three-hybrid assay Lindwasser et al. GFP was used as an indicator for transfected cells.
Nef complex are unknown, but this model suggests that the binding would likely be tighter than for these isolated components, and the off rate correspondingly slower. Figure 4 doesn’t really help much because it shows zike Nef interaction footprint, but doesn’t show the positions of any residues.
Other residues implicated in CD4 binding, including Leu97, Arg, and Leu, also project into the bowl Grzesiek et al. The general proximity of Nef, and its N-terminal region in particular, to the membrane is similar to the model proposed for the AP