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Remarkably low affi...
Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions
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- Jönsson, Peter (author)
- Lund University,Lunds universitet,Fysikalisk kemi,Enheten för fysikalisk och teoretisk kemi,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Physical Chemistry,Physical and theoretical chemistry,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,University of Cambridge
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- Southcombe, Jennifer H. (author)
- University of Oxford
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- Mafalda Santos, Ana (author)
- University of Oxford
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- Huo, Jiandong (author)
- University of Oxford
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- Fernandes, Ricardo A. (author)
- University of Oxford
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- McColl, James (author)
- University of Cambridge
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- Lever, Melissa (author)
- University of Oxford
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- Evans, Edward J. (author)
- University of Oxford
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- Hudson, Alexander (author)
- University of Oxford
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- Chang, Veronica T. (author)
- University of Oxford
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- Hanke, Tomáš (author)
- University of Oxford
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- Godkin, Andrew (author)
- Cardiff University
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- Dunne, Paul D. (author)
- University of Cambridge
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- Horrocks, Mathew H. (author)
- University of Cambridge
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- Palayret, Matthieu (author)
- University of Cambridge
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- Screaton, Gavin R. (author)
- University of Oxford
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- Petersen, Jan (author)
- Monash University
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- Rossjohn, Jamie (author)
- Cardiff University,Monash University
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- Fugger, Lars (author)
- University of Oxford
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- Dushek, Omer (author)
- University of Oxford
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- Xu, Xiao Ning (author)
- University of Oxford
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- Davis, Simon J. (author)
- University of Oxford
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- Klenerman, David (author)
- University of Cambridge
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(creator_code:org_t)
- 2016-04-25
- 2016
- English 6 s.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 113:20, s. 5682-5687
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Abstract
Subject headings
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- The αβ T-cell coreceptor CD4 enhances immune responses more than 1 million-fold in some assays, and yet the affinity of CD4 for its ligand, peptide-major histocompatibility class II (pMHC II) on antigen-presenting cells, is so weak that it was previously unquantifiable. Here, we report that a soluble form of CD4 failed to bind detectably to pMHC II in surface plasmon resonance-based assays, establishing a new upper limit for the solution affinity at 2.5 mM. However, when presented multivalently on magnetic beads, soluble CD4 bound pMHC II-expressing B cells, confirming that it is active and allowing mapping of the native coreceptor binding site on pMHC II. Whereas binding was undetectable in solution, the affinity of the CD4/pMHC II interaction could be measured in 2D using CD4- and adhesion molecule-functionalized, supported lipid bilayers, yielding a 2D Kd of ∼5,000 molecules/μm2. This value is two to three orders of magnitude higher than previously measured 2D Kd values for interacting leukocyte surface proteins. Calculations indicated, however, that CD4/pMHC II binding would increase rates of T-cell receptor (TCR) complex phosphorylation by threefold via the recruitment of Lck, with only a small, 2-20% increase in the effective affinity of the TCR for pMHC II. The affinity of CD4/pMHC II therefore seems to be set at a value that increases T-cell sensitivity by enhancing phosphorylation, without compromising ligand discrimination.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- Adhesion
- Binding equilibrium and kinetics
- Protein interactions
- T-cell activation
- TCR phosphorylation
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Jönsson, Peter
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Southcombe, Jenn ...
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Mafalda Santos, ...
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Huo, Jiandong
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Fernandes, Ricar ...
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McColl, James
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show more...
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Lever, Melissa
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Evans, Edward J.
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Hudson, Alexande ...
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Chang, Veronica ...
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Hanke, Tomáš
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Godkin, Andrew
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Dunne, Paul D.
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Horrocks, Mathew ...
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Palayret, Matthi ...
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Screaton, Gavin ...
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Petersen, Jan
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Rossjohn, Jamie
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Fugger, Lars
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Dushek, Omer
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Xu, Xiao Ning
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Davis, Simon J.
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Klenerman, David
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show less...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biochemistry and ...
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Proceedings of t ...
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Lund University