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Cryo-EM structure of a membrane protein(CS)
Structural highlights
DiseaseCD3Z_HUMAN Defects in CD247 are the cause of immunodeficiency due to defect in CD3-zeta (CD3ZID) [MIM:610163. An immunological deficiency characterized by T-cells impaired immune response to alloantigens, tetanus toxoid and mitogens.[1] FunctionCD3Z_HUMAN Probable role in assembly and expression of the TCR complex as well as signal transduction upon antigen triggering. Publication Abstract from PubMedCholesterol molecules specifically bind to the resting alphabetaTCR to inhibit cytoplasmic CD3zeta ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. The structures reveal that cholesterol molecules act like a latch to lock CD3zeta into an inactive conformation in the membrane. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3zeta transmembrane helix, thereby activating the TCR-CD3 complex in human cells. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex. Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.,Chen Y, Zhu Y, Li X, Gao W, Zhen Z, Dong D, Huang B, Ma Z, Zhang A, Song X, Ma Y, Guo C, Zhang F, Huang Z Mol Cell. 2022 Apr 7;82(7):1278-1287.e5. doi: 10.1016/j.molcel.2022.02.017. Epub , 2022 Mar 9. PMID:35271814[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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