3tvm
Structure of the mouse CD1d-SMC124-iNKT TCR complex
Structural highlights
DiseaseTRAC_HUMAN TCR-alpha-beta-positive T-cell deficiency. The disease is caused by variants affecting the gene represented in this entry. FunctionTRAC_HUMAN Constant region of T cell receptor (TR) alpha chain (PubMed:24600447). Alpha-beta T cell receptors are antigen specific receptors which are essential to the immune response and are present on the cell surface of T lymphocytes. Recognize peptide-major histocompatibility (MH) (pMH) complexes that are displayed by antigen presenting cells (APC), a prerequisite for efficient T cell adaptive immunity against pathogens (PubMed:25493333). Binding of alpha-beta TR to pMH complex initiates TR-CD3 clustering on the cell surface and intracellular activation of LCK that phosphorylates the ITAM motifs of CD3G, CD3D, CD3E and CD247 enabling the recruitment of ZAP70. In turn, ZAP70 phosphorylates LAT, which recruits numerous signaling molecules to form the LAT signalosome. The LAT signalosome propagates signal branching to three major signaling pathways, the calcium, the mitogen-activated protein kinase (MAPK) kinase and the nuclear factor NF-kappa-B (NF-kB) pathways, leading to the mobilization of transcription factors that are critical for gene expression and essential for T cell growth and differentiation (PubMed:23524462). The T cell repertoire is generated in the thymus, by V-(D)-J rearrangement. This repertoire is then shaped by intrathymic selection events to generate a peripheral T cell pool of self-MH restricted, non-autoaggressive T cells. Post-thymic interaction of alpha-beta TR with the pMH complexes shapes TR structural and functional avidity (PubMed:15040585).[1] [2] [3] [4] Publication Abstract from PubMedNatural killer T (NKT) cells recognize glycolipids presented by CD1d. The first antigen described, alpha-galactosyl ceramide (alphaGalCer), is a potential anticancer agent whose activity depends upon IFN-gamma secretion. We report two analogs of alphaGalCer based on a naturally occurring glycosphingolipid, plakoside A. These compounds induce enhanced IFN-gamma that correlates with detergent-resistant binding to CD1d and an increased stability of the lipid-CD1d complexes on antigen-presenting cells. Structural analysis on one of the analogs indicates that it is more deeply bound inside the CD1d groove, suggesting tighter lipid-CD1d interactions. To our knowledge, this is the first example in which structural information provides an explanation for the increased lipid-CD1d stability, likely responsible for the Th1 bias. We provide insights into the mechanism of IFN-gamma-inducing compounds, and because our compounds activate human NKT cells, they could have therapeutic utility. Glycolipids that Elicit IFN-gamma-Biased Responses from Natural Killer T Cells.,Tyznik AJ, Farber E, Girardi E, Birkholz A, Li Y, Chitale S, So R, Arora P, Khurana A, Wang J, Porcelli SA, Zajonc DM, Kronenberg M, Howell AR Chem Biol. 2011 Dec 23;18(12):1620-30. PMID:22195564[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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