PMID: 20944746

 

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Title : The structural basis for autonomous dimerization of the pre-T-cell antigen receptor

Abstract :
  1. The pre-T-cell antigen receptor (pre- TCR ), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR β- selection, survival and proliferation of CD4 (-)CD8(-) double-negative thymocytes, and subsequent αβ T-cell lineage differentiation
  2. Whereas αβ TCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling, pre- TCR-induced signalling occurs by means of a ligand-independent dimerization event
  3. The pre- TCR comprises an invariant α -chain (pre-Tα) that pairs with any TCR β-chain ( TCRβ) following successful TCR β-gene rearrangement
  4. Here we provide the basis of pre-Tα- TCRβ assembly and pre- TCR dimerization
  5. The pre-Tα chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR α- chain; nevertheless, the mode of association between pre-Tα and TCRβ mirrored that mediated by the Cα-Cβ domains of the αβ TCR
  6. The pre- TCR had a propensity to dimerize in solution, and the molecular envelope of the pre- TCR dimer correlated well with the observed head-to-tail pre- TCR dimer
  7. This mode of pre- TCR dimerization enabled the pre-Tα domain to interact with the variable (V) β domain through residues that are highly conserved across the Vβ and joining (J) β gene families, thus mimicking the interactions at the core of the αβ TCR 's Vα-Vβ interface
  8. Disruption of this pre-Tα-Vβ dimer interface abrogated pre- TCR dimerization in solution and impaired pre- TCR expression on the cell surface
  9. Accordingly, we provide a mechanism of pre- TCR self-association that allows the pre-Tα chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR β-chain , regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development
  10. This unusual dual-chaperone-like sensing function of pre-Tα represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex