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J. Biol. Chem., Vol. 279, Issue 30, 31717-31726, July 23, 2004

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Structural Basis of the Substrate-specific Two-step Catalysis of Long Chain Fatty Acyl-CoA Synthetase Dimer^*

Yuko Hisanaga¶, Hideo Ago||**, Noriko Nakagawa, Keisuke Hamada, Koh Ida, Masaki Yamamoto¶¶, Tetsuya Hori, Yasuhiro Arii, Mitsuaki Sugahara||, Seiki Kuramitsu, Shigeyuki Yokoyama, and Masashi Miyano||||||

From the Structural Biophysics Laboratory, the ^||Highthroughput Factory, the Structurome Research Group, and the ^¶¶Coherent X-ray Optics Laboratory, RIKEN Harima Institute at SPring-8, Kouto, Mikazuki, Sayo, Hyogo 679-5148, Japan, the Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan, and the Graduate School of Integrated Science, Yokohama City University, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

Long chain fatty acyl-CoA synthetases are responsible for fatty acid degradation as well as physiological regulation of cellular functions via the production of long chain fatty acyl-CoA esters. We report the first crystal structures of long chain fatty acyl-CoA synthetase homodimer (LC-FACS) from Thermus thermophilus HB8 (ttLC-FACS), including complexes with the ATP analogue adenosine 5'-(,-imido) triphosphate (AMP-PNP) and myristoyl-AMP. ttLC-FACS is a member of the adenylate forming enzyme superfamily that catalyzes the ATP-dependent acylation of fatty acid in a two-step reaction. The first reaction step was shown to propagate in AMP-PNP complex crystals soaked with myristate solution. Myristoyl-AMP was identified as the intermediate. The AMP-PNP and the myristoyl-AMP complex structures show an identical closed conformation of the small C-terminal domains, whereas the uncomplexed form shows a variety of open conformations. Upon ATP binding, the fatty acid-binding tunnel gated by an aromatic residue opens to the ATP-binding site. The gated fatty acid-binding tunnel appears only to allow one-way movement of the fatty acid during overall catalysis. The protein incorporates a hydrophobic branch from the fatty acid-binding tunnel that is responsible for substrate specificity. Based on these high resolution crystal structures, we propose a unidirectional Bi Uni Uni Bi Ping-Pong mechanism for the two-step acylation by ttLC-FACS.

Received for publication, January 6, 2004 , and in revised form, May 13, 2004.

The atomic coordinates and structure factors (codes 1ULT, 1V25 and 1V26) 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 in part by the National project on protein structural and functional analysis funded by 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

^¶ Present address: Dept. of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.

^** To whom correspondence may be addressed. Tel.: 81-791-58-2815; Fax: 81-791-58-2816; E-mail: ago{at}spring8.or.jp. |||| To whom correspondence may be addressed. Tel.: 81-791-58-2815; Fax: 81-791-58-2816; E-mail: miyano{at}spring8.or.jp.

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