Molecular Interactions of Endogenous d-myo-Inositol Phosphates with the Intracellular d-myo-Inositol 1,4,5-Trisphosphate Recognition Site

Pei Jung Lu, Da Ming Gou, Woan Ru Shieh, Ching Shih Chen

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

A systematic effort was made to elucidate the mode of recognition at the inositol 1,4,5- trisphosphate-specific receptor. Eleven D-myo-inositol phosphates were synthesized and tested for Ca2+- mobilizing and receptor-binding activities, which included Ins(1,3,4,5,6)P5, Ins(1,2,5,6)P4, Ins(l,3,4,5)P4, Ins(l,3,4,6)P4, Ins(l,4,5,6)P4, Ins(3,4,5,6)P4, Ins(l,3,4)P3, Ins(l,4,5)P3, Ins(l,5,6)P3, Ins(l,4)P2, and Ins- (4,5)P2- Of these, Ins(l,4,5)P3, Ins(l,3,4,6)P4, Ins(1,3,4,5)P4, Ins(1,4,5,6)P4, and Ins(4,5)P2 were able to elicit Ca2+ release from rat brain microsomes. Binding experiments suggest that the ability of these polyphosphates to effect Ca2+ mobilization arises from interactions with the Ins(1,4,5)P3-specific receptor. Accordingly, a model accounting for the ligand recognition is proposed. The Ins(1,4,5)P3-binding site is presumably composed of two domains. The anchoring domain binds the 4,5-bisphosphate 6-hydroxy motif. Disruption of this structural feature abolishes the agonist activity. The auxiliary domain exerts long-range interactions with the 1-phosphate, thus enhancing the binding affinity. The stereochemical requirement for this electrostatic interaction is, however, less stringent. Evidence suggests that Ca2+-mobilizing inositol phosphates are able to effect productive binding by assuming conformations displaying or mimicking these essential structural features.

Original languageEnglish
Pages (from-to)11586-11597
Number of pages12
JournalBiochemistry
Volume33
Issue number38
DOIs
Publication statusPublished - 1994 Sep 1

All Science Journal Classification (ASJC) codes

  • Biochemistry

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