A beta-sheet interaction interface directs the tetramerisation of the Miz-1 POZ domain.
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 A 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.
Stead
Mark A
MA
Molecular Cell Biology Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Garstang/Astbury Buildings, Leeds LS2 9JT, UK.
Trinh
Chi H
CH
Garnett
James A
JA
Carr
Stephen B
SB
Baron
Andrew J
AJ
Edwards
Thomas A
TA
Wright
Stephanie C
SC
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D016335:Zinc Fingers
D051741:Kruppel-Like Transcription Factors; C107961:ZBTB17 protein, human