7kx0
Crystal structure of the CD27:CD70 co-stimulatory complex
Structural highlights
DiseaseCD70_HUMAN Combined immunodeficiency due to CD70 deficiency. The disease is caused by variants affecting the gene represented in this entry. FunctionCD70_HUMAN Expressed at the plasma membrane of B cells, it is the ligand of the CD27 receptor which is specifically expressed at the surface of T cells (PubMed:28011863, PubMed:28011864, PubMed:8387892). The CD70-CD27 signaling pathway mediates antigen-specific T cell activation and expansion which in turn provides immune surveillance of B cells (PubMed:28011863, PubMed:28011864).[1] [2] [3] Publication Abstract from PubMedCD27 is a tumor necrosis factor (TNF) receptor, which stimulates lymphocytes and promotes their differentiation upon activation by TNF ligand CD70. Activation of the CD27 receptor provides a costimulatory signal to promote T cell, B cell, and NK cell activity to facilitate antitumor and anti-infection immunity. Aberrant increased and focused expression of CD70 on many tumor cells renders CD70 an attractive therapeutic target for direct tumor killing. However, despite their use as drug targets to treat cancers, the molecular basis and atomic details of CD27 and CD70 interaction remain elusive. Here we report the crystal structure of human CD27 in complex with human CD70. Analysis of our structure shows that CD70 adopts a classical TNF ligand homotrimeric assembly to engage CD27 receptors in a 3:3 stoichiometry. By combining structural and rational mutagenesis data with reported disease-correlated mutations, we identified the key amino acid residues of CD27 and CD70 that control this interaction. We also report increased potency for plate-bound CD70 constructs compared with solution-phase ligand in a functional activity to stimulate T-cells in vitro. These findings offer new mechanistic insight into this critical costimulatory interaction. Structural delineation and phase-dependent activation of the costimulatory CD27:CD70 complex.,Liu W, Maben Z, Wang C, Lindquist KC, Li M, Rayannavar V, Lopez Armenta I, Nager A, Pascua E, Dominik PK, Oyen D, Wang H, Roach RC, Allan CM, Mosyak L, Chaparro-Riggers J J Biol Chem. 2021 Oct;297(4):101102. doi: 10.1016/j.jbc.2021.101102. Epub 2021 , Aug 20. PMID:34419446[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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