Insights into Fanconi Anaemia from the structure of human FANCE.
Fanconi Anaemia (FA) is a cancer predisposition disorder characterized by spontaneous chromosome breakage and high cellular sensitivity to genotoxic agents. In response to DNA damage, a multi-subunit assembly of FA proteins, the FA core complex, monoubiquitinates the downstream FANCD2 protein. The FANCE protein plays an essential role in the FA process of DNA repair as the FANCD2-binding component of the FA core complex. Here we report a crystallographic and biological study of human FANCE. The first structure of a FA protein reveals the presence of a repeated helical motif that provides a template for the structural rationalization of other proteins defective in Fanconi Anaemia. The portion of FANCE defined by our crystallographic analysis is sufficient for interaction with FANCD2, yielding structural information into the mode of FANCD2 recruitment to the FA core complex. Disease-associated mutations disrupt the FANCE-FANCD2 interaction, providing structural insight into the molecular mechanisms of FA pathogenesis.
Nookala
Ravi K
RK
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1GA, UK.
Hussain
Shobbir
S
Pellegrini
Luca
L
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000737:chemistry / Q000378:metabolism; D052239:Fanconi Anemia Complementation Group E Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
C499907:FANCE protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein