8T4Z

T-cell receptor and lipid complex structure

Summary for 8T4Z

• Entry DOI: 10.2210/pdb8t4z/pdb
• Descriptor: Antigen-presenting glycoprotein CD1d1, Beta-2-microglobulin, T cell receptor alpha variable 11, Human nkt tcr alpha chain chimera, ... (8 entities in total)
• Functional Keywords: mhc-like protein, lipid binding protein, antigen-presenting molecule
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 4
• Total formula weight: 98461.11

Authors

Praveena, T.,Rossjohn, J. (deposition date: 2023-06-12, release date: 2024-08-07, Last modification date: 2024-10-30)

Primary citation

Cheng, T.Y.,Praveena, T.,Govindarajan, S.,Almeida, C.F.,Pellicci, D.G.,Arkins, W.C.,Van Rhijn, I.,Venken, K.,Elewaut, D.,Godfrey, D.I.,Rossjohn, J.,Moody, D.B.
Lipidomic scanning of self-lipids identifies headless antigens for natural killer T cells.
Proc.Natl.Acad.Sci.USA, 121:e2321686121-e2321686121, 2024

PubMed Abstract: To broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.

PubMed: 39141352
DOI: 10.1073/pnas.2321686121

Experimental method

X-RAY DIFFRACTION (2.691 Å)