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Structural Analysis of Human FANCL, the E3 Ligase in the Fanconi Anemia Pathway

DOI: 10.1074/jbc.M111.244632 DOI Help
PMID: 21775430 PMID Help

Authors: Charlotte Hodson (London Research Institute, Cancer Research UK) , Ambrose Cole (London Research Institute, Cancer Research UK) , Laurence Lewis (London Research Institute, Cancer Research UK) , Jennifer Miles (London Research Institute, Cancer Research UK) , Andrew Purkiss (London Research Institute, Cancer Research UK) , Helen Walden (London Research Institute, Cancer Research UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 286 (37) , PAGES 32628 - 32637

State: Published (Approved)
Published: September 2011
Diamond Proposal Number(s): 6385

Abstract: The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand cross-links. At the heart of this pathway is the monoubiquitination of the FANCI-FANCD2 (ID) complex by the multiprotein “core complex” containing the E3 ubiquitin ligase FANCL. Vertebrate organisms have the eight-protein core complex, whereas invertebrates apparently do not. We report here the structure of the central domain of human FANCL in comparison with the recently solved Drosophila melanogaster FANCL. Our data represent the first structural detail into the catalytic core of the human system and reveal that the central fold of FANCL is conserved between species. However, there are macromolecular differences between the FANCL proteins that may account for the apparent distinctions in core complex requirements between the vertebrate and invertebrate FA pathways. In addition, we characterize the binding of human FANCL with its partners, Ube2t, FANCD2, and FANCI. Mutational analysis reveals which residues are required for substrate binding, and we also show the domain required for E2 binding.

Journal Keywords: Drosophila; Fanconi; Fanconi; Fanconi; Humans; Mutation; Peptide; Protein; Quaternary; Protein; Tertiary; Ubiquitin-Conjugating Enzymes

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 29/09/2011 16:27

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