Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding

Regulatory factor X (RFX) proteins are transcriptional activators that recognize X-boxes (DNA of the sequence 5'-GTNRCC(0-3N) RGYAAC-3', where N is any nucleotide, R is a purine and Y is a pyrimidine) using a highly conserved 76-residue DNA-binding domain (DBD). DNA-binding defects in the protein RFX5 cause bare lymphocyte syndrome or major histocompatibility antigen class II defciency(1), RFXI, -2 and -3 regulate expression of other medically important gene products (for example, interleukin-5 receptor alpha chain, IL-5R alpha)(2). Fusions of the ligand-binding domain of the oestrogen receptor with the DBD of RFX4 occur in some human breast tumours'. Here we present a 1.5 Angstrom-resolution structure of two copies of the DBD of human RFXI (hRFX1) binding cooperatively to a symmetrical X-box(4,5), hRFX1 is an unusual member of the winged-helix subfamily of helix-turn-helix proteins(6) because it uses a beta-hairpin (or wing) to recognize DNA instead of the recognition helix typical of helix-turn-helix proteins. A new model for interactions between linker histones and DNA is proposed.