Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains.
Plant homeodomain (PHD) domains are found in >400 eukaryotic proteins, many of which are transcriptional regulators. Naturally occurring point mutations or deletions of this domain contribute to a variety of human diseases, including ATRX syndrome, myeloid leukemias and autoimmune dysfunction. Here we report the first structural characterization of a PHD domain. Our studies reveal that the PHD domain from KAP-1 corepressor binds zinc in a cross-brace topology between anti-parallel ss-strands reminiscent of RING (really interesting new gene) domains. Using a mutational analysis, we define the structural features required for transcriptional repression by KAP-1 and explain naturally occurring, disease-causing mutations in PHD domains of other proteins. From a comparison of this PHD structure with previously reported RING and LIM (Lin11/Isl-1/Mec-3) structures, we infer sequence determinants that allow discrimination among PHD, RING and LIM motifs.
Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.
A D
AD
Capili
D C
DC
Schultz
F J
FJ
RauscherIII
K L
KL
Borden
D000595:Amino Acid Sequence; D001665:Binding Sites; D003196:Computer Graphics; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D010940:Plant Proteins / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D000076183:Tripartite Motif-Containing Protein 28; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D010940:Plant Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28