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Molecular and Cellular Biology, November 2008, p. 6828-6843, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01297-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Molecular Architecture of Quartet MOZ/MORF Histone Acetyltransferase Complexes{triangledown} ,§

Mukta Ullah,1,2,3 Nadine Pelletier,1,2 Lin Xiao,1,2 Song Ping Zhao,1 Kainan Wang,1,3 Cindy Degerny,1,2 Soroush Tahmasebi,1,2 Christelle Cayrou,4 Yannick Doyon,4 Siew-Lee Goh,1 Nathalie Champagne,1 Jacques Côté,4 and Xiang-Jiao Yang1,2,3*

Department of Medicine, McGill University Health Centre,1 McGill Cancer Centre,2 Department of Biochemistry, McGill University, Montréal, Québec, Canada,3 Laval University Cancer Research Center, Hôtel-Dieu de Quebec (CHUQ), Québec City, Québec, Canada4

Received 14 August 2008/ Accepted 8 September 2008

The monocytic leukemia zinc finger protein MOZ and the related factor MORF form tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3. To gain new insights into the structure, function, and regulation of these complexes, we reconstituted them and performed various molecular analyses. We found that BRPF proteins bridge the association of MOZ and MORF with ING5 and EAF6. An N-terminal region of BRPF1 interacts with the acetyltransferases; the enhancer of polycomb (EPc) homology domain in the middle part binds to ING5 and EAF6. The association of BRPF1 with EAF6 is weak, but ING5 increases the affinity. These three proteins form a trimeric core that is conserved from Drosophila melanogaster to humans, although authentic orthologs of MOZ and MORF are absent in invertebrates. Deletion mapping studies revealed that the acetyltransferase domain of MOZ/MORF is sufficient for BRPF1 interaction. At the functional level, complex formation with BRPF1 and ING5 drastically stimulates the activity of the acetyltransferase domain in acetylation of nucleosomal histone H3 and free histones H3 and H4. An unstructured 18-residue region at the C-terminal end of the catalytic domain is required for BRPF1 interaction and may function as an "activation lid." Furthermore, BRPF1 enhances the transcriptional potential of MOZ and a leukemic MOZ-TIF2 fusion protein. These findings thus indicate that BRPF proteins play a key role in assembling and activating MOZ/MORF acetyltransferase complexes.

* Corresponding author. Mailing address: McGill Cancer Centre, Cancer Pavilion, Room 408, 1160 Pine Avenue West, Montréal, Québec H3G 0B1, Canada. Phone: (514) 398-5883. Fax: (514) 398-6769. E-mail: xiang-jiao.yang{at}mcgill.ca

{triangledown} Published ahead of print on 15 September 2008.

§ Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2008, p. 6828-6843, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.01297-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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