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

Pang, Siew Siew, Berry, Richard, Chen, Zhenjun, Kjer-Nielsen, Lars, Perugini, Matthew A., King, Glenn F., Wang, Christina, Chew, Sock Hui, La Gruta, Nicole L., Williams, Neal K., Beddoe, Travis, Tiganis, Tony, Cowieson, Nathan P., Godfrey, Dale I., Purcell, Anthony W., Wilce, Matthew C. J., McCluskey, James and Rossjohn, Jamie 2010. The structural basis for autonomous dimerization of the pre-T-cell antigen receptor. Nature 467 (7317) , pp. 844-848. 10.1038/nature09448

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Abstract

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 differentiation1, 2, 3. Whereas αβTCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling4, pre-TCR-induced signalling occurs by means of a ligand-independent dimerization event5. The pre-TCR comprises an invariant α-chain (pre-Tα) that pairs with any TCR β-chain (TCRβ) following successful TCR β-gene rearrangement6. Here we provide the basis of pre-Tα–TCRβ assembly and pre-TCR dimerization. The pre-Tα chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR α-chain7; nevertheless, the mode of association between pre-Tα and TCRβ mirrored that mediated by the Cα–Cβ domains of the αβTCR. 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. 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 αβTCR’s Vα–Vβ interface. Disruption of this pre-Tα–Vβ dimer interface abrogated pre-TCR dimerization in solution and impaired pre-TCR expression on the cell surface. 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. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QR Microbiology > QR180 Immunology
Publisher: Nature Publishing Group
ISSN: 0028-0836
Last Modified: 04 Jun 2017 05:06
URI: http://orca-mwe.cf.ac.uk/id/eprint/48465

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