Structural insights into the regulatory mechanism of inositol 1,4,5-trisphosphate receptor.
Published: 2005
Language: eng
Number of pages: 180
Description: In a variety of cells Ca2+ signaling processes such as Ca2+ oscillation are mediated by the ER membrane-associated Ca2+ release channel, inositol 1,4,5-trisphosphate receptor (IP3R). IP3R plays a vital role in the control of cellular and physiological processes as diverse as cell division, cell proliferation, apoptosis, fertilization, development, behavior, memory and learning. Opening of the Ca2+ release channel requires sequential binding of two intracellular messengers IP3 and Ca2+. I have determined the crystal structure of the receptor IP3-binding core in complex with IP3. The structure consists of two asymmetric domains, one with the beta-trefoil fold and the other possessing an 'armadillo-like' repeats. The cleft formed by the two domains exposes a cluster of arginine and lysine residues that coordinate the three phosphoryl groups of IP 3. Putative Ca2+ binding sites are identified in two separate locations within the IP3-binding core. More recently I determined the crystal structure of the IP3 binding suppression domain, which includes the first 220 residues directly preceding the IP 3-binding core domain. The conserved surface on one side of the suppressor domain appears to interact with the IP3-binding core domain. Interestingly, this surface is in close proximity to the previously proposed binding sites of Homer, RACK1, calmodulin, and CaBP1. Structural information for the IP 3R N-terminus sheds light onto the mechanism underlying the receptor's sensitivity to the IP3 molecule and its communication with cellular signaling proteins.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5272.

Thesis (Ph.D.)--University of Toronto, 2005.

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