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TitleCholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.
Journal, issue, pagesMol Cell, Vol. 82, Issue 7, Page 1278-11287.e5, Year 2022
Publish dateApr 7, 2022
AuthorsYan 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 AbstractCholesterol 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.
External linksMol Cell / PubMed:35271814
MethodsEM (single particle)
Resolution3.0 - 3.2 Å
Structure data

31618

7fjd

EMDB-31618, PDB-7fjd:
Cryo-EM structure of a membrane protein(WT)
Method: EM (single particle) / Resolution: 3.2 Å

31619

7fje

EMDB-31619, PDB-7fje:
Cryo-EM structure of a membrane protein(LL)
Method: EM (single particle) / Resolution: 3.0 Å

31620

7fjf

EMDB-31620, PDB-7fjf:
Cryo-EM structure of a membrane protein(CS)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-C3S:
CHOLEST-5-EN-3-YL HYDROGEN SULFATE / Cholesterol sulfate

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / membrane / immune

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