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 mutatio ns or deletions of this domain contribute to a variety of human diseases, i ncluding ATRX syndrome, myeloid leukemias and autoimmune dysfunction, Here we report the first structural characterization of a PHD domain, Our studie s reveal that the PHD domain from KAP-1 corepressor binds zinc in a cross-b race topology between anti-parallel beta -strands reminiscent of RING (real ly interesting new gene) domains. Using a mutational analysis, we define th e structural features required for transcriptional repression by KAP-1 and explain naturally occurring, disease-causing mutations in PHD domains of ot her proteins. From a comparison of this PHD structure with previously repor ted RING and LIM (Lin11Isl-1/Mec-3) structures, we infer sequence determina nts that allow discrimination among PHD, RING and LIM motifs.