8vse
Cryo-EM structure of human CD45 extracellular region in complex with adenoviral protein E3/49K
Structural highlights
DiseasePTPRC_HUMAN T-B+ severe combined immunodeficiency due to CD45 deficiency. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility may be associated with variations affecting the gene represented in this entry. FunctionPTPRC_HUMAN Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity). Publication Abstract from PubMedCD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as "beads on a string" that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses. Orientation-dependent CD45 inhibition with viral and engineered ligands.,Borowska MT, Liu LD, Caveney NA, Jude KM, Kim WJ, Masubuchi T, Hui E, Majzner RG, Garcia KC Sci Immunol. 2024 Oct 25;9(100):eadp0707. doi: 10.1126/sciimmunol.adp0707. Epub , 2024 Oct 25. PMID:39454026[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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