DNA recognition by the MYST family of histone acetyltransferases: Structure/function characterization of the human monocytic leukemia zinc finger protein MOZ.

摘要

Human monocytic leukemia zinc-finger protein (MOZ) is a member of the MYST subfamily of histone acetyltransferases (HATs) involved in human pathogenesis, specifically oncogenic transformation leading to acute myeloid leukemia.{09}Acute myeloid leukemias (AML) are characterized by the expression of fusion genes involving transcriptional coactivators, including MOZ, that are a result of chromosomal translocations. The MOZ-containing gene fusion products that are characteristic of AML all contain the conserved catalytic HAT domain of MOZ underscoring a possible significant role for aberrant acetylation in human leukemias.; The functional and structural studies presented here characterize the conserved MYST domain of MOZ and unveil the first enzymatic protein domain that can also bind DNA. The crystal structure of the MYST domain of MOZ complexed to acetyl-coenzyme A is presented and subsequent structural and biochemical analysis reveals two putative DNA-binding motifs, a zinc-finger and helix-turn-helix. The DNA-binding property of the MOZ HAT domain was discovered to be a protein dependent function inherent to the MOZ HAT domain and not an evolutionarily conserved function of other MYST family HAT domains, or even other broadly classified HAT domains. In vitro evidence demonstrates that the MOZ HAT domain directly participates in nucleosome targeting through its DNA recognition domains. The HAT domain of MOZ preferentially acetylates nucleosomes at a greater rate than not only other MYST family members but also other HAT enzymes. This evidence suggests that the DNA-binding activity of MOZ occurs through a previously undiscovered cooperative mechanism involving the two DNA-binding motifs proposed here that further act to stimulate histone acetylation.; This is the first report of a multifunctional chromatin regulatory domain containing both enzymatic and chromatin targeting activities. These studies provide further mechanistic insight into the acetylation and subsequent histone and nucleosomal substrate targeting of MOZ, a physiologically relevant model of MOZ function in transcriptional activation, and a structural model for the rational design of small molecule inhibitors that may alleviate the aberrant acetylation characteristic of leukemias.