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

Nature volume 467, pages 844–848 (2010)Cite this article

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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.

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Figure 1: The pre-Tα structure.
Figure 2: Comparison between the pre-TCR and αβTCR structures.
Figure 3: The pre-TCR dimer.
Figure 4: Pre-TCR dimerization in solution.
Figure 5: Expression of pre-TCR mutants.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates and structure factors of pre-TCR have been deposited in the Protein Data Bank under the accession code 3OF6.

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Acknowledgements

We thank S. Turner for discussions; S. Ramarathinam for technical assistance; the staff at the Australian synchrotron (MX and SAXS/WAXS beamlines) and Berkeley Advanced Light Source (SIBYLS beamline) for assistance with data collection; and T. Caradoc-Davies for advice on processing of merohedral twinned X-ray data. This research was supported by grants from the Australian Research Council and the National Health and Medical Research Council of Australia. A.W.P., T.T. and M.C.J.W. are supported by NHMRC Senior Research Fellowships, and D.I.G. is supported by an NHMRC Principal Research Fellowship. M.A.P. is supported by an ARC Future Fellowship and J.R. is supported by an ARC Federation Fellowship.

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Author notes

  1. Nathan P. Cowieson

    Present address: Present address: The Australian Synchrotron, Blackburn Road, Monash, Clayton, Victoria 3168, Australia.,

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, School of Biomedical Sciences, Monash University, Clayton, 3800, Victoria, Australia

    Siew Siew Pang, Richard Berry, Christina Wang, Sock Hui Chew, Neal K. Williams, Travis Beddoe, Tony Tiganis, Nathan P. Cowieson, Matthew C. J. Wilce & Jamie Rossjohn

  2. Department of Microbiology & Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Zhenjun Chen, Lars Kjer-Nielsen, Nicole L. La Gruta, Dale I. Godfrey & James McCluskey

  3. Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, 3010, Victoria, Australia

    Matthew A. Perugini & Anthony W. Purcell

  4. Division of Chemistry & Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, 4072, Queensland, Australia

    Glenn F. King

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Contributions

S.S.P. solved the structure, undertook analysis, performed experiments and contributed to manuscript preparation. J.M., D.I.G. and J.R. contributed to the design and interpretation of experiments, project management and the writing of the manuscript. R.B., Z.C., L.K.-N., M.A.P., G.F.K., N.L.L.G., T.T. and A.W.P. performed experiments and contributed to the writing of the manuscript; C.W., S.H.C., N.K.W., T.B., N.P.C. and M.C.J.W. performed experiments. J.M. and J.R. were the joint senior authors—they co-led the investigation, devised the project, analysed the data and wrote the manuscript.

Corresponding authors

Correspondence to James McCluskey or Jamie Rossjohn.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-8 with legends and Supplementary Tables 1-6. (PDF 4983 kb)

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Pang, S., Berry, R., Chen, Z. et al. The structural basis for autonomous dimerization of the pre-T-cell antigen receptor. Nature 467, 844–848 (2010). https://doi.org/10.1038/nature09448

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