期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 14, 页码 4372-4380出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.AC119.011747
关键词
protein structure; immunotherapy; T-cell biology; protein evolution; glycoprotein structure; immune checkpoint; immune receptors; ligands; PD-L2; programmed cell death protein 1 (PD-1); programmed death ligand 1 (PD-L1)
资金
- National Institutes of Health [T32AR069515, T32GM007308, R01AI125640]
- Ministerio de Economia y Competitividad FIS Grant [PI16/00504]
Programmed cell death protein 1 (PD-1) is an inhibitory receptor on T lymphocytes that is critical for modulating adaptive immunity. As such, it has been successfully exploited for cancer immunotherapy. Programmed death ligand 1 (PD-L1) and PD-L2 are ligands for PD-1; the former is ubiquitously expressed in inflamed tissues, whereas the latter is restricted to antigen-presenting cells. PD-L2 binds to PD-1 with 3-fold stronger affinity compared with PD-L1. To date, this affinity discrepancy has been attributed to a tryptophan (W110(PD-L2)) that is unique to PD-L2 and has been assumed to fit snuggly into a pocket on the PD-1 surface. Contrary to this model, using surface plasmon resonance to monitor real-time binding of recombinantly-expressed and -purified proteins, we found that W110(PD-L2) acts as an ?elbow? that helps shorten PD-L2 engagement with PD-1 and therefore lower affinity. Furthermore, we identified a ?latch? between the C and D ?-strands of the binding face as the source of the PD-L2 affinity advantage. We show that the 3-fold affinity advantage of PD-L2 is the consequence of these two opposing features, the W110(PD-L2) ?elbow? and a C?D region ?latch.? Interestingly, using phylogenetic analysis, we found that these features evolved simultaneously upon the emergence of placental mammals, suggesting that PD-L2?affinity tuning was part of the alterations to the adaptive immune system required for placental gestation.
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