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The structure of the catalytic subunit FANCL of the Fanconi anemia core complex

Nature Structural & Molecular Biology volume 17, pages 294–298 (2010)Cite this article

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Abstract

The Fanconi anemia (FA) pathway is activated in response to DNA damage, leading to monoubiquitination of the substrates FANCI and FANCD2 by the FA core complex. Here we report the crystal structure of FANCL, the catalytic subunit of the FA core complex, at 3.2 Å. The structure reveals an architecture fundamentally different from previous sequence-based predictions. The molecule is composed of an N-terminal E2-like fold, which we term the ELF domain, a novel double-RWD (DRWD) domain, and a C-terminal really interesting new gene (RING) domain predicted to facilitate E2 binding. Binding assays show that the DRWD domain, but not the ELF domain, is responsible for substrate binding.

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Figure 1: Domain architecture of FANCL.
Figure 2: Comparison of UBC-superfamily folds with E2s and RWD proteins.
Figure 3: Protein-protein interaction surfaces on FANCL.
Figure 4: The DRWD domain recruits substrate.

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Protein Data Bank

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Acknowledgements

We thank M. Way and F. Pinto for help with improving the manuscript, V. Chaugule for critical comments, discussion and technical assistance, L. Wood for assistance with sequence analysis and S. Kjaer and S. Kisakye-Nambozo of the Protein Production Facility for generation of the baculoviruses and subsequent Sf9 infection. All authors are funded by Cancer Research UK.

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Authors and Affiliations

  1. Protein Structure and Function Laboratory, Lincoln's Inn Fields Laboratories of the London Research Institute, Cancer Research UK, London Research Institute, London, UK

    Ambrose R Cole, Laurence P C Lewis & Helen Walden

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  1. Ambrose R Cole
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  2. Laurence P C Lewis
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  3. Helen Walden
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Contributions

A.R.C. crystallized, solved, refined and analyzed the FANCL structure and performed the biochemical experiments. All authors cloned, expressed and purified proteins. H.W. designed and supervised the study. A.R.C. and H.W. wrote the manuscript.

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Correspondence to Helen Walden.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Supplementary Tables 1–6 (PDF 7227 kb)

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Cole, A., Lewis, L. & Walden, H. The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nat Struct Mol Biol 17, 294–298 (2010). https://doi.org/10.1038/nsmb.1759

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