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J. Biol. Chem., Vol. 283, Issue 20, 14022-14031, May 16, 2008

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Crystal Structures of Fission Yeast Histone Chaperone Asf1 Complexed with the Hip1 B-domain or the Cac2 C Terminus^*

Ali D. Malay¹, Takashi Umehara, Kazuko Matsubara-Malay, Balasundaram Padmanabhan², and Shigeyuki Yokoyama³

From the Yokohama Institute, RIKEN, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045 and the Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

The assembly of core histones onto eukaryotic DNA is modulated by several histone chaperone complexes, including Asf1, CAF-1, and HIRA. Asf1 is a unique histone chaperone that participates in both the replication-dependent and replication-independent pathways. Here we report the crystal structures of the apo-form of fission yeast Asf1/Cia1 (SpAsf1N; residues 1-161) as well as its complexes with the B-domain of the fission yeast HIRA orthologue Hip1 (Hip1B) and the C-terminal region of the Cac2 subunit of CAF-1 (Cac2C). The mode of the fission yeast Asf1N-Hip1B recognition is similar to that of the human Asf1-HIRA recognition, suggesting that Asf1N recognition of Hip1B/HIRA is conserved from yeast to mammals. Interestingly, Hip1B and Cac2C show remarkably similar interaction modes with Asf1. The binding between Asf1N and Hip1B was almost completely abolished by the D37A and L60A/V62A mutations in Asf1N, indicating the critical role of salt bridge and van der Waals contacts in the complex formation. Consistently, both of the aforementioned Asf1 mutations also drastically reduced the binding to Cac2C. These results provide a structural basis for a mutually exclusive Asf1-binding model of CAF-1 and HIRA/Hip1, in which Asf1 and CAF-1 assemble histones H3/H4 (H3.1/H4 in vertebrates) in a replication-dependent pathway, whereas Asf1 and HIRA/Hip1 assemble histones H3/H4 (H3.3/H4 in vertebrates) in a replication-independent pathway.

Received for publication, January 23, 2008

The atomic coordinates and structure factors (code 2CU9, 2Z34, and 2Z3F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the RIKEN Structural Genomics/Proteomics Initiative, the National Project on Protein Structural and Functional Analyses, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Global Edge Inst., Tokyo Inst. of Technology, 4259, B-36, Nagatsuda, Midori-ku, Yokohama, Kanagawa, 226-8501, Japan.

² To whom correspondence may be addressed: Aptuit Laurus Private Ltd., ICICI Knowledge Park, Shameerpet, Hyderabad 500 078, India. Tel.: 91-40-23480480; Fax: 91-40-23480481; E-mail: paddy.b{at}aptuitlaurus.com.

³ To whom correspondence may be addressed: Yokohama Inst., RIKEN, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan. Tel.: 81-45-503-9196; Fax: 81-45-503-9195; E-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp.

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