A Beta-Sheet Interaction Interface Directs the Tetramerisation of the Miz-1 POZ Domain

• Published in: Journal of molecular biology Vol. 373; no. 4; pp. 820 - 826
• Main Authors: Stead, Mark A., Trinh, Chi H., Garnett, James A., Carr, Stephen B., Baron, Andrew J., Edwards, Thomas A., Wright, Stephanie C.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 02.11.2007
• Subjects: Amino Acid Sequence; BCL6; BTB domain; c-Myc; Crystallography, X-Ray - methods; Dimerization; Humans; Kruppel-Like Transcription Factors - chemistry; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Models, Molecular; Molecular Sequence Data; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Zinc Fingers; POZ/BTB; LRF; BCL6; c-Myc; HECTH9; BTB domain; SMRT; TOPBP1; Miz-1; PLZF; PDB
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2007.08.026

The POZ/BTB domain is an evolutionarily conserved motif found in approximately 40 zinc-finger transcription factors (POZ-ZF factors). Several POZ-ZF factors are implicated in human cancer, and POZ domain interaction interfaces represent an attractive target for therapeutic intervention. Miz-1 ( Myc- interacting zinc-finger protein) is a POZ-ZF factor that regulates DNA-damage-induced cell cycle arrest and plays an important role in human cancer by virtue of its interaction with the c-Myc and BCL6 oncogene products. The Miz-1 POZ domain mediates both self-association and the recruitment of non-POZ partners. POZ-ZF factors generally function as homodimers, although higher-order associations and heteromeric interactions are known to be physiologically important; crucially, the interaction interfaces in such large complexes have not been characterised. We report here the crystal structure of the Miz-1 POZ domain up to 2.1 Å resolution. The tetrameric organisation of Miz-1 POZ reveals two types of interaction interface between subunits; an interface of alpha-helices resembles the dimerisation interface of reported POZ domain structures, whereas a novel beta-sheet interface directs the association of two POZ domain dimers. We show that the beta-sheet interface directs the tetramerisation of the Miz-1 POZ domain in solution and therefore represents a newly described candidate interface for the higher-order homo- and hetero-oligomerisation of POZ-ZF proteins in vivo.