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Link to original content: https://doi.org/10.1038/nsb725
Crystal structure of an Xrcc4–DNA ligase IV complex | Nature Structural & Molecular Biology
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Crystal structure of an Xrcc4–DNA ligase IV complex

Nature Structural Biology volume 8, pages 1015–1019 (2001)Cite this article

Abstract

A complex of two proteins, Xrcc4 and DNA ligase IV, plays a fundamental role in DNA non-homologous end joining (NHEJ), a cellular function required for double-strand break repair and V(D)J recombination. Here we report the crystal structure of human Xrcc4 bound to a polypeptide that corresponds to the DNA ligase IV sequence linking its two BRCA1 C-terminal (BRCT) domains. In the complex, a single ligase chain binds asymmetrically to an Xrcc4 dimer. The helical tails of Xrcc4 undergo a substantial conformational change relative to the uncomplexed protein, forming a coiled coil that unwinds upon ligase binding, leading to a flat interaction surface. A buried network of charged hydrogen bonds surrounded by extensive hydrophobic contacts explains the observed tightness of the interaction. The strong conservation of residues at the interface between the two proteins provides evidence that the observed mode of interaction has been maintained in NHEJ throughout evolution.

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Figure 1: Interaction between DNA ligase IV and Xrcc4.
Figure 2: Features of Xrcc4–DNA ligase IV complex.
Figure 3: Evolutionary conservation of amino acids responsible for the Xrcc4–DNA ligase IV interaction.
Figure 4: The protein–protein interface of the human Xrcc4–DNA ligase IV complex.

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Acknowledgements

We would like to thank G. Robbins for early work on Xrcc4, and E. Gordon, S. McSweeney, G. Leonard and E. Mitchell for excellent technical assistance at the ESRF beamlines. This research was supported by grants from the Wellcome Trust.

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Author notes

  1. Susan E. Critchlow

    Present address: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK

  2. Jake Begun

    Present address: Harvard Medical School, Boston, Massachusetts, 02115, USA

Authors and Affiliations

  1. Department of Biochemistry, Cambridge University, Tennis Court Road, Cambridge, CB2 1GA, UK

    Bancinyane L. Sibanda, Jake Begun, Xue Y. Pei, Tom L. Blundell & Luca Pellegrini

  2. The Wellcome/CRC Institute, Cambridge University, Tennis Court Road, Cambridge, CB2 1QR, UK

    Susan E. Critchlow & Stephen P. Jackson

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Correspondence to Luca Pellegrini.

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Sibanda, B., Critchlow, S., Begun, J. et al. Crystal structure of an Xrcc4–DNA ligase IV complex. Nat Struct Mol Biol 8, 1015–1019 (2001). https://doi.org/10.1038/nsb725

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