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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Mariuzza, Roy A. Wang, Lili Li, Yili Gao, Wei Mo, Min Wang, Qian Wang, Xin Xiang Yin, Yiyuan |
| Description | Author Affiliation: Wang XX ( W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.); |
| Abstract | Helper T-cell activation generally requires the coreceptor CD4, which binds MHC class II molecules. A remarkable feature of the CD4-MHC class II interaction is its exceptionally low affinity, which ranges from K(D) = â ¼200 µM to >2 mM. Investigating the biological role of the much lower affinity of this interaction than those of other cell-cell recognition molecules will require CD4 mutants with enhanced binding to MHC class II for testing in models of T-cell development. To this end, we used in vitro-directed evolution to increase the affinity of human CD4 for HLA-DR1. A mutant CD4 library was displayed on the surface of yeast and selected using HLA-DR1 tetramers or monomers, resulting in isolation of a CD4 clone containing 11 mutations. Reversion mutagenesis showed that most of the affinity increase derived from just two substitutions, Gln40Tyr and Thr45Trp. A CD4 variant bearing these mutations bound HLA-DR1 with K(D) = 8.8 µM, compared with >400 µM for wild-type CD4. To understand the basis for improved affinity, we determined the structure of this CD4 variant in complex with HLA-DR1 to 2.4 Å resolution. The structure provides an atomic-level description of the CD4-binding site on MHC class II and reveals how CD4 recognizes highly polymorphic HLA-DR, -DP, and -DQ molecules by targeting invariant residues in their 2 and ß2 domains. In addition, the CD4 mutants reported here constitute unique tools for probing the influence of CD4 affinity on T-cell activation and development. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 38 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antigens, CD4 Chemistry HLA-DR1 Antigen Protein Conformation Protein Structure, Tertiary Amino Acid Sequence Animals Genetics Metabolism Binding Sites Binding, Competitive Cell Line Crystallization Crystallography, X-Ray HIV Envelope Protein Gp120 Models, Molecular Mutation Peptide Library Protein Binding Protein Multimerization Sequence Homology, Amino Acid Spodoptera Surface Plasmon Resonance Yeasts Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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