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J. Biol. Chem., Vol. 278, Issue 52, 52881-52889, December 26, 2003

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Three-dimensional Rearrangements within Inositol 1,4,5-Trisphosphate Receptor by Calcium^*

Kozo Hamada¶, Akiko Terauchi, and Katsuhiko Mikoshiba||¶

From the Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan, Calcium Oscillation Project, International Cooperative Research Project (ICORP), Japan Science and Technology Agency (JST), 3-14-4, Shirokanedai, Minato-ku, Tokyo 108-0071, Japan, and ^||Department of Basic Medical Sciences, Division of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Allosteric binding of calcium ion (Ca²⁺) to inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) controls channel gating within IP₃R. Here, we present biochemical and electron microscopic evidence of Ca²⁺-sensitive structural changes in the three-dimensional structure of type 1 IP₃R (IP₃R1). Low concentrations of Ca²⁺ and high concentrations of Sr²⁺ and Ba²⁺ were shown to be effective for the limited proteolysis of IP₃R1, but Mg²⁺ had no effect on the proteolysis. The electron microscopy and the limited proteolysis consistently demonstrated that the effective concentration of Ca²⁺ for conformational changes in IP₃R1 was <10^-7 M and that the IP₃ scarcely affected the conformational states. The structure of IP₃R1 without Ca²⁺, as reconstructed by three-dimensional electron microscopy, had a "mushroom-like" appearance consisting of a large square-shaped head and a small channel domain linked by four thin bridges. The projection image of the "head-to-head" assembly comprising two particles confirmed the mushroom-like side view. The "windmill-like" form of IP₃R1 with Ca²⁺ also contains the four bridges connecting from the IP₃-binding domain toward the channel domain. These data suggest that the Ca²⁺-specific conformational change structurally regulates the IP₃-triggered channel opening within IP₃R1.

Received for publication, September 3, 2003 , and in revised form, October 27, 2003.

^* 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.

^¶ To whom correspondence may be addressed. Tel: 81-3-5449-5316; Fax: 81-3-5449-5420; E-mail: mikosiba{at}ims.u-tokyo.ac.jp or hamada{at}ims.u-tokyo.ac.jp.

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