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Structure and Interactions of the Human Programmed Cell Death 1 Receptor

Cheng, Xiaoxiao ; Veverka, Vaclav ; Radhakrishnan, Anand ; Waters, Lorna C. ; Muskett, Frederick W. ; Morgan, Sara H. ; Huo, Jiandong ; Yu, Chao ; Evans, Edward J. ; Leslie, Alasdair J. ; Griffiths, Meryn ; Stubberfield, Colin ; Griffin, Robert ; Henry, Alistair J. ; Jansson, Andreas ; Ladbury, John E. ; Ikemizu, Shinji ; Carr, Mark D. ; Davis, Simon J.

The Journal of biological chemistry, 2013-04, Vol.288 (17), p.11771-11785 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Structure and Interactions of the Human Programmed Cell Death 1 Receptor
Autor: Cheng, Xiaoxiao ; Veverka, Vaclav ; Radhakrishnan, Anand ; Waters, Lorna C. ; Muskett, Frederick W. ; Morgan, Sara H. ; Huo, Jiandong ; Yu, Chao ; Evans, Edward J. ; Leslie, Alasdair J. ; Griffiths, Meryn ; Stubberfield, Colin ; Griffin, Robert ; Henry, Alistair J. ; Jansson, Andreas ; Ladbury, John E. ; Ikemizu, Shinji ; Carr, Mark D. ; Davis, Simon J.
Assuntos: Affinity ; Animals ; Antigen-Presenting Cells - chemistry ; Antigen-Presenting Cells - immunology ; Antigen-Presenting Cells - metabolism ; B7-1 Antigen - chemistry ; B7-1 Antigen - genetics ; B7-1 Antigen - immunology ; B7-1 Antigen - metabolism ; B7-H1 Antigen - chemistry ; B7-H1 Antigen - genetics ; B7-H1 Antigen - immunology ; B7-H1 Antigen - metabolism ; Cell Communication - immunology ; Cell Surface Protein ; Complex Formation ; Humans ; Immunology ; Mice ; Models, Immunological ; Natural sciences ; Naturvetenskap ; Nuclear Magnetic Resonance ; Nuclear Magnetic Resonance, Biomolecular ; Programmed Cell Death 1 Ligand 2 Protein - chemistry ; Programmed Cell Death 1 Ligand 2 Protein - genetics ; Programmed Cell Death 1 Ligand 2 Protein - immunology ; Programmed Cell Death 1 Ligand 2 Protein - metabolism ; Programmed Cell Death 1 Receptor - chemistry ; Programmed Cell Death 1 Receptor - genetics ; Programmed Cell Death 1 Receptor - immunology ; Programmed Cell Death 1 Receptor - metabolism ; Protein Binding ; Protein Structure, Secondary ; Receptors ; Signaling ; Structure-Activity Relationship ; Surface Plasmon Resonance ; Surface Plasmon Resonance (SPR) ; T-Lymphocytes - chemistry ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Thermodynamics
É parte de: The Journal of biological chemistry, 2013-04, Vol.288 (17), p.11771-11785
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Both authors contributed equally to this work.
Descrição: 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. Background: The inhibitory leukocyte receptor PD-1 binds two ligands, PD-L1 and PD-L2. Results: Nuclear magnetic resonance analysis and rigorous binding and thermodynamic measurements reveal the structure of, and the mode of ligand recognition by, PD-1. Conclusion: PD-L1 and PD-L2 bind differently to PD-1 and much more weakly than expected. Significance: Potent inhibitory signaling can be initiated by weakly interacting receptors.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Structure and Interactions of the Human Programmed Cell Death 1 Receptor

United States: Elsevier Inc

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