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| Title | Orientation-dependent CD45 inhibition with viral and engineered ligands. |
|---|---|
| Journal, issue, pages | Sci Immunol, Vol. 9, Issue 100, Page eadp0707, Year 2024 |
| Publish date | Oct 25, 2024 |
 Authors | Marta T Borowska / Liu D Liu / Nathanael A Caveney / Kevin M Jude / Won-Ju Kim / Takeya Masubuchi / Enfu Hui / Robbie G Majzner / K Christopher Garcia /  |
| PubMed Abstract | CD45 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 ...CD45 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. |
 External links | Sci Immunol / PubMed:39454026 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.8 Å |
| Structure data | EMDB-43497, PDB-8vse: |
| Chemicals |  ChemComp-NAG: |
| Source |
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 Keywords | IMMUNE SYSTEM / Complex / T cell signaling / Viral suppression |
homo sapiens (human)
human adenovirus 19a