TitleCritical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors.
Publication TypeJournal Article
Year of Publication2002
AuthorsMelnick, Ari, Carlile Graeme, K Ahmad Farid, Kiang Chih-Li, Corcoran Connie, Bardwell Vivian, Prive Gilbert G., and Licht Jonathan D.
JournalMol Cell Biol
Date Published2002 Mar
KeywordsAmino Acid Motifs, Cell Line, Dimerization, DNA-Binding Proteins, Histone Deacetylase 1, Histone Deacetylases, Humans, Kruppel-Like Transcription Factors, Molecular Sequence Data, Mutagenesis, Site-Directed, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2, Promyelocytic Leukemia Zinc Finger Protein, Protein Structure, Tertiary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Sequence Homology, Amino Acid, Structure-Activity Relationship, Transcription Factors, Transcription, Genetic, Transfection, Two-Hybrid System Techniques

<p>The PLZF (promyelocytic leukemia zinc finger) transcriptional repressor, when fused to retinoic acid receptor alpha (RARalpha), causes a refractory form of acute promyelocytic leukemia. The highly conserved N-terminal BTB (bric a brac, tramtrack, broad complex)/POZ domain of PLZF plays a critical role in this disease, since it is required for transcriptional repression by the PLZF-RARalpha fusion protein. The crystal structure of the PLZF BTB domain revealed an obligate homodimer with a highly conserved charged pocket formed by apposition of the two monomers. An extensive structure-function analysis showed that the charged pocket motif plays a major role in transcriptional repression by PLZF. We found that mutations of the BTB domain that neutralize key charged pocket residues did not disrupt dimerization, yet abrogated the ability of PLZF to repress transcription and led to the loss of interaction with N-CoR, SMRT, and histone deacetylases (HDACs). We extended these studies to the Bcl-6 protein, which is linked to the pathogenesis of non-Hodgkin's lymphomas. In this case, neutralizing the charged pocket also resulted in loss of repression and corepressor binding. Experiments with purified protein showed that corepressor-BTB interactions were direct. A comparison of the PLZF, Bcl-6, and the FAZF (Fanconi anemia zinc finger)/ROG protein shows that variations in the BTB pocket result in differential affinity for corepressors, which predicts the potency of transcriptional repression. Thus, the BTB pocket represents a molecular structure involved in recruitment of transcriptional repression complexes to target promoters.</p>

Alternate JournalMol Cell Biol
PubMed ID11865059
PubMed Central IDPMC135611
Grant ListR01 CA059936 / CA / NCI NIH HHS / United States
K08 CA 73762 / CA / NCI NIH HHS / United States
R29 CA071540 / CA / NCI NIH HHS / United States
R01 CA 59936 / CA / NCI NIH HHS / United States
R29 CA 71540 / CA / NCI NIH HHS / United States
R01 CA071540 / CA / NCI NIH HHS / United States