January 12, 2019 posted by

Protein Expression and Purification. FACS analysis was performed as described before Chaudhuri et al. Mutational analysis of HIV-1 Nef: Schematics are shown to the right of A and B. This provides insight into the underlying reason for the unusual architecture of Nef, as a single domain protein with disproportionately large internal loops. Table 2 is a nice summary of the different mutational analyses, but it doesn’t explain the structural role of any of the mutated residues.

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Human immunodeficiency virus type 1 Nef protein targets CD4 to the multivesicular body pathway. We aie the chance to highlight this important comparison, and we have added a new Figure 8 incorporating this suggestion. Figure 4 and Table 2 have been extensively annotated following this excellent suggestion.

To elucidate the structural basis for this interaction, we have solved the crystal structure at 2.

How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4

Moreover, since these sites are not susceptible to rapid mutations, such drugs are less likely to encounter the problem of drug resistance. Support Center Support Center. Kildall at Digital Research.

Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4. Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity. The description will focus on the B, C, and D chains, for which the Nef: National Center for Biotechnology InformationU.


Statistics of crystallographic data collection and refinement DOI: A model for the membrane-bound AP An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown.

– c99 shell

A highly concave pocket specific for the Nef interaction. William F SchmidtA. Please review our privacy policy.

Akie funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Altered T cell activation and development in transgenic mice expressing the HIV-1 nef gene. This information could be used c09 develop drugs that work by blocking the amino residues on AP-2 that bind to Nef.

Direct in vitro binding of full-length human immunodeficiency virus type 1 Nef protein to CD4 cytoplasmic domain.

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Your article has been favorably evaluated by a Senior editor and 3 peer reviewers, one of whom is a member of the Board of Reviewing Editors. The dissociation constants for CD4: We performed additional mutagenesis to test for the functional importance of residues that were newly identified by the structure determination Figures 5 and 6.

These results can now be mapped onto the structure Figure 4. Similarly, the author response typically shows only responses to the major concerns raised by the reviewers. Refined solution structure and backbone dynamics of HIV-1 Nef. AP-2 complex interacts with the cytosolic tail of CD4, leading to the cooperative assembly of a tripartite Nef: AhoWeinbergerKernighan.


The Journal of Infectious Diseases. Measurements were repeated three times and carried out on an itc instrument MicroCal, Northampton, MA.

How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4

The core also manifests a poorly ordered N-terminal helix H1 spanning residues 55—65, which was not visualized in all of the chains. The dileucine peptide in the unlatched structure Kelly et al. Hydrogen bonds occur between the side chain of Asp and the main-chain amide NH of Gln, and between the side-chains of Nef Asp and Arg Additional files Major dataset The following dataset was generated: The Nef-AP-2 interaction is so central auke CD4 downregulation that it has inspired exhaustive mutational analyses Aiken et al.