Molecular flexibility can influence the stimulatory ability of receptor-ligand interactions at cell-cell junctions

被引:42
作者
Qi, SY
Krogsgaard, M
Davis, MM [1 ]
Chakraborty, AK
机构
[1] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA
[2] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA
[3] Univ Calif Berkeley, Dept Chem Engn, Berkeley, CA 94720 USA
[4] MIT, Dept Chem Engn, Cambridge, MA 02139 USA
[5] MIT, Dept Chem, Cambridge, MA 02139 USA
[6] MIT, Div Biol Engn, Cambridge, MA 02139 USA
关键词
conformational changes; lymphocyte activation; receptor-ligand binding;
D O I
10.1073/pnas.0510991103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Direct cell-cell communication is crucial for many processes in biology, particularly embryogenesis, interactions between hematopoetic cells, and in the nervous system. This communication is often mediated by the binding of receptors to cognate ligands at a cell-cell junction. One such interaction that is very important for the development of many immune responses is the binding of the alpha beta T cell receptor for antigen (TCR) on T lymphocytes with peptide-MHC complexes on other cells. In general, the stability (e.g., half-life) of TCR-peptide-MHC binding measured in solution correlates with functional responses. Several anomalies have been reported, however. For example, for some anomalous ligands, large changes in heat capacity can apparently substitute for a lack of stability in TCR-ligand interactions. Here, we show that, when there are significant conformational changes during receptor-ligand binding and the receptor/ligand have relatively rigid molecular subdomains, the difference between the half-life of this receptor-ligand complex at a cell-cell junction and that measured using soluble molecules is large. Thus, receptors/ligands with these specific molecular features do not follow correlations between stimulatory potency in the cellular environment and half-lives measured with soluble molecules. Our "first-principles" prescription for correcting the half-life measured in solution to obtain the pertinent value at a cell-cell junction illuminates the origin of correlations of T cell response with thermodynamic properties. Application of our ideas to diverse systems where receptor-ligand interactions occur across juxtaposed cells may help avoid debates about "anomalies" that may simply arise from receptor/ligand-specific differences between half-lives in solution and in the cellular environment.
引用
收藏
页码:4416 / 4421
页数:6
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