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Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand

Abstract

In a variety of cells, the Ca2+ signalling process is mediated by the endoplasmic-reticulum-membrane-associated Ca2+ release channel, inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R)1. Being ubiquitous and present in organisms ranging from humans to Caenorhabditis elegans, InsP3R has a vital role in the control of cellular and physiological processes as diverse as cell division, cell proliferation, apoptosis, fertilization, development, behaviour, memory and learning2. Mouse type I InsP3R (InsP3R1), found in high abundance in cerebellar Purkinje cells, is a polypeptide with three major functionally distinct regions: the amino-terminal InsP3-binding region, the central modulatory region and the carboxy-terminal channel region2. Here we present a 2.2-Å crystal structure of the InsP3-binding core of mouse InsP3R1 in complex with InsP3. The asymmetric, boomerang-like structure consists of an N-terminal β-trefoil domain and a C-terminal α-helical domain containing an ‘armadillo repeat’-like fold. The cleft formed by the two domains exposes a cluster of arginine and lysine residues that coordinate the three phosphoryl groups of InsP3. Putative Ca2+-binding sites are identified in two separate locations within the InsP3-binding core.

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Figure 1: Overall domain architecture of InsP3R and sequence alignment of the InsP3-binding core between members of the InsP3R family.
Figure 2: Structure of mouse InsP3R1c in complex with InsP3.
Figure 3: β-Trefoil and ‘armadillo repeat’-like folds in mouse InsP3R1c.
Figure 4: Coordination of InsP3 by mouse InsP3R1c.

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Acknowledgements

We thank A. Nakagawa, A. Miyazaki and K.T. Chong for their assistance at the beamline BL44XU at SPring-8, Japan; the staff at the X8-C and X25 beamline of Brookhaven National Laboratory and the BioCars beamline at Advanced Photon Source for their assistance; D. Jones and M. Swindells for mGenTHREADER analysis; and members of our division for discussions. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to I.B. and M.I., and by grants from RIKEN (to K.M.) and the Ministry of Education, Science, Sports, and Culture of Japan (to K.M. and T.M.). M.I. is a CIHR Investigator.

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Bosanac, I., Alattia, JR., Mal, T. et al. Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420, 696–700 (2002). https://doi.org/10.1038/nature01268

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