Lecture 14: TCR Structure and Signalling Flashcards
Recall the properties of TCR.
Most T cells recognize the peptide/MHC complex using a ______________.
Recall the interaction within the TCR signalling complex.
The positively charged residues on the transmembrane region of the TCR interacts with the negative shared residues of the CD3 complex. Charged residues in the transmembrane domain of each subunit form polar interactions allowing a correct and stable assembly of the complex. The CD3 complex has ITAMs, which mediate activation of TCR.
Recall the BCR signalling complex
Recall the γδ TCR.
Recall the similarities between Ig and TCR genes.
In T cells, alpha + beta genes have undergone ________________. In other cells, TCR genes are in ______________.
somatic recombination
germline configuration.
Recall the similarities between TCR and BCR VDJ recombination.
TCR genes undergo SMH. True or False.
False
Recall the TCR gene loci.
5’ => 3’
Recall the diagram showing beta-chain somatic recombination.
Recall the CDR3 region of the TCR chains.
Recall the diversity generation of TCR.
Recall the TCR footprint on MHC class I molecules.
The structurally equivalent third hypervariable loops of the T-cell receptor α and β chains, to which the D and J gene segments contribute, also form the center of the antigen-binding site of a T-cell receptor; the periphery of the site consists of the CDR1 and CDR2 loops, which are encoded within the germline V gene segments for the α and β chains.
Recall the orientation and positioning of the TCR on MHC class I molecules
The structurally equivalent third hypervariable loops of the T-cell receptor α and β chains, to which the D and J gene segments contribute, also form the center of the antigen-binding site of a T-cell receptor; the periphery of the site consists of the CDR1 and CDR2 loops, which are encoded within the germline V gene segments for the α and β chains.
Recall the overview of the TCR/BCR signalling pathway.
The first detectable events following antigen receptor stimulation are the activation of tyrosine kinases. Following this, adaptor proteins and scaffolds are modified, recruiting phospholipases and lipid kinases to the activated receptor complexes. The next level of signalling amplifies these earlier stages by activating multiple small GTPases, serine/threonine kinases, and protein phosphatases. Together, these lead to transcription factor activation, cytoskeletal changes, and increases in cellular adhesion and metabolism, all of which contribute to T- and B-cell activation.
Recall the regulation of Lck (Src family kinase)
The Lck bound to the cytoplasmic tails of CD4 or CD8 is brought near its substrate ITAMs in the T-cell receptor when the co-receptor binds the receptor:peptide:MHC complex.
Lck’s activity is also regulated allosterically by phosphorylation of a tyrosine in its carboxy terminus by the C-terminal Src kinase (Csk). The resulting phosphotyrosine interacts with Lck’s SH2 domain and helps maintain Lck in a closed conformation, resulting in a catalytically inactive state
In nonstimulated lymphocytes, phosphorylation of Lck is counteracted by the tyrosine phosphatase CD45, which can dephosphorylate both of the Lck tyrosine phosphorylation sites. Dephosphorylation of the carboxy-terminal tyrosine by the releases the SH2 and 3 domain, priming it.
Lck is fully activated when its activation loop tyrosine in the kinase domain is autophosphorylated
Recall the activation of ZAP-70.
Signaling from the T-cell receptor is initiated by tyrosine phosphorylation within cytoplasmic regions called immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3ε, γ, δ, and ζ chains.
Each ITAM contains two tyrosine residues that become phosphorylated by specific protein tyrosine kinases (such as Lck) when the receptor binds its ligand, providing sites for the recruitment of the SH2 domains of signaling proteins, such as ZAP-70.
Lck is constitutively associated with ______ and _______. Lck phosphorylates the _____ in the TCR upon co-receptor engagement with antigen:MHC.
______________ provide a docking site for the activation of ZAP-70.
Activated ZAP-70 phosphorylates _________ and ____________ and promotes ______ activation.
LAT and SLP-76
PI3-Kinase
Recall the four signalling molecules activated through the action of ZAP-70 and their functions.
Activated Zap-70 phosphorylates the scaffold proteins LAT and SLP-76 and recruits them to the activated T-cell receptor (TcR) complex. one key component required for several of these modules is the activation of PI3-kinase, which phosphorylates PIP2 in the plasma membrane to generate pip
PLC-gamma activation leads to _______________.
transcription factor activation
Note: IL-2 gene - T cell survival gene
Recall TCR alpha and beta chain receptor rearrangement.
Recall the TCR complex.
Activation of PLC-gamma requires _______________________.
While naive T- and B-cell activation requires signalling through the antigen receptors on these cells, T-cell receptor or B-cell receptor signalling, respectively, is not sufficient to activate the cells. For naive T cells, an additional co-stimulatory signal is required and, as discussed above, is frequently provided by the CD28 receptor.
