Structural determinants of human FANCF protein that function in the assembly of a DNA damage signaling complex.
Fanconi anemia (FA) is a rare autosomal recessive and X-linked chromosomal instability disorder. At least eight FA proteins (FANCA, B, C, E, F, G, L, and M) form a nuclear core complex required for monoubiquitination of a downstream protein, FANCD2. The human FANCF protein reportedly functions as a molecular adaptor within the FA nuclear complex, bridging between the subcomplexes A:G and C:E. Our x-ray crystallographic studies of the C-terminal domain of FANCF reveal a helical repeat structure similar to the Cand1 regulator of the Cul1-Rbx1-Skp1-Fbox(Skp2) ubiquitin ligase complex. Two C-terminal loops of FANCF are essential for monoubiquitination of FANCD2 and normal cellular resistance to the DNA cross-linking agent mitomycin C. FANCF mutants bearing amino acid substitutions in this C-terminal surface fail to interact with other components of the FA complex, indicating that this surface is critical for the proper assembly of the FA core complex.
Kowal
Przemyslaw
P
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Gurtan
Allan M
AM
Stuckert
Patricia
P
D'Andrea
Alan D
AD
Ellenberger
Tom
T
D000595:Amino Acid Sequence; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D052219:Fanconi Anemia Complementation Group F Protein / Q000737:chemistry*; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry
C486317:CAND1 protein, human; C499901:FANCF protein, human; D052219:Fanconi Anemia Complementation Group F Protein; D014157:Transcription Factors; D025801:Ubiquitin; D016685:Mitomycin