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-Structure paper
タイトル | Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility. |
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ジャーナル・号・ページ | Mol Cell, Vol. 82, Issue 7, Page 1278-11287.e5, Year 2022 |
掲載日 | 2022年4月7日 |
![]() | Yan Chen / Yuwei Zhu / Xiang Li / Wenbo Gao / Ziqi Zhen / De Dong / Buliao Huang / Zhuo Ma / Anqi Zhang / Xiaocui Song / Yan Ma / Changyou Guo / Fan Zhang / Zhiwei Huang / ![]() |
PubMed 要旨 | Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms ...Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ 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 CD3ζ 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 CD3ζ 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. |
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手法 | EM (単粒子) |
解像度 | 3.0 - 3.2 Å |
構造データ | EMDB-31618, PDB-7fjd: EMDB-31619, PDB-7fje: EMDB-31620, PDB-7fjf: |
化合物 | ![]() ChemComp-CLR: ![]() ChemComp-C3S: |
由来 |
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![]() | IMMUNE SYSTEM / membrane / immune |