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, Neil 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: 844-848. doi:10.1038/nature09448


Author 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, Neil K.
Beddoe, Travis
Tiganis, Tony
Cowieson, Nathan P.
Godfrey, Dale I.
Purcell, Anthony W.
Wilce, Matthew C. J.
McCluskey, James
Rossjohn, Jamie
Title The structural basis for autonomous dimerization of the pre-T-cell antigen receptor
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
1476-4687
Publication date 2010-10-14
Year available 2010
Sub-type Article (original research)
DOI 10.1038/nature09448
Open Access Status Not yet assessed
Volume 467
Issue 7317
Start page 844
End page 848
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 2700 Medicine
1000 General
Abstract The pre-T-cell antigen receptor (pre-TCR), expressed by immature thymocytes, has a pivotal role in early T-cell development, including TCR beta-selection, survival and proliferation of CD4(-)CD8(-) double-negative thymocytes, and subsequent ab T-cell lineage differentiation(1-3). Whereas alpha beta TCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling(4), preTCR-induced signalling occurs by means of a ligand-independent dimerization event(5). The pre-TCR comprises an invariant a-chain (pre-T alpha) that pairs with any TCR beta-chain (TCR beta) following successful TCR beta-gene rearrangement(6). Here we provide the basis of pre-T alpha-TCR beta assembly and pre-TCR dimerization. The pre-T alpha chain comprised a single immunoglobulin-like domain that is structurally distinct from the constant (C) domain of the TCR alpha-chain(7); nevertheless, the mode of association between pre-T alpha and TCRb mirrored that mediated by the C alpha-C beta domains of the abTCR. 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-T alpha domain to interact with the variable (V) beta domain through residues that are highly conserved across the V beta and joining (J) beta gene families, thus mimicking the interactions at the core of the alpha beta TCR's V alpha-V beta interface. Disruption of this pre-T alpha-V beta 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-T alpha chain to simultaneously 'sample' the correct folding of both the V and C domains of any TCR beta-chain, regardless of its ultimate specificity, which represents a critical checkpoint in T-cell development. This unusual dual-chaperone-like sensing function of pre-T alpha represents a unique mechanism in nature whereby developmental quality control regulates the expression and signalling of an integral membrane receptor complex.
Formatted 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 differentiation1-3. Whereas αβTCR ligation by the peptide-loaded major histocompatibility complex initiates T-cell signalling 4, pre- TCR-induced signalling occurs by means of a ligand-independent dimerization event5. The pre-TCR comprises an invariant α-chain (pre-Ta) 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. © 2010 Macmillan Publishers Limited. All rights reserved.
Keyword Scattering
Sedimentation-velocity
Angstrom
Alpha
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published under Letters

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 31 Oct 2010, 10:03:34 EST