0392809 - ÚOCHB 2014 RIV US eng J - Článek v odborném periodiku
Cheng, X. X. - Veverka, Václav - Radhakrishnan, A. - Waters, L. C. - Muskett, F. W. - Morgan, S. H. - Huo, J. D. - Yu, C. - Evans, E. J. - Leslie, A. J. - Griffiths, M. - Stubberfield, C. - Griffin, R. - Henry, A. J. - Jansson, A. - Ladbury, J. E. - Ikemizu, S. - Carr, M. D. - Davis, S. J.
Structure and Interactions of the Human Programmed Cell Death 1 Receptor.
Journal of Biological Chemistry. Roč. 288, č. 17 (2013), s. 11771-11785. ISSN 0021-9258. E-ISSN 1083-351X
Institucionální podpora: RVO:61388963
Klíčová slova: cell surface protein * N-terminal domain * T-cells * nucear magnetic resonance * PD-1 expression
Kód oboru RIV: CE - Biochemie
Impakt faktor: 4.600, rok: 2013

PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C '' strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1.ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.
Trvalý link: http://hdl.handle.net/11104/0221575