7Z3J

Structure of crystallisable rat Phospholipase C gamma 1 in complex with inositol 1,4,5-trisphosphate

7Z3J の概要

• エントリーDOI: 10.2210/pdb7z3j/pdb
• 分子名称: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1, CALCIUM ION, D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: hydrolase complex autoinhibited state, hydrolase
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 136767.47

構造登録者

Pinotsis, N.,Bunney, T.D.,Katan, M. (登録日: 2022-03-02, 公開日: 2022-07-20, 最終更新日: 2024-10-23)

主引用文献

Le Huray, K.I.P.,Bunney, T.D.,Pinotsis, N.,Kalli, A.C.,Katan, M.
Characterization of the membrane interactions of phospholipase C gamma reveals key features of the active enzyme.
Sci Adv, 8:eabp9688-eabp9688, 2022

PubMed Abstract: PLCγ enzymes are autoinhibited in resting cells and form key components of intracellular signaling that are also linked to disease development. Insights into physiological and aberrant activation of PLCγ require understanding of an active, membrane-bound form, which can hydrolyze inositol-lipid substrates. Here, we demonstrate that PLCγ1 cannot bind membranes unless the autoinhibition is disrupted. Through extensive molecular dynamics simulations and experimental evidence, we characterize membrane binding by the catalytic core domains and reveal previously unknown sites of lipid interaction. The identified sites act in synergy, overlap with autoinhibitory interfaces, and are shown to be critical for the phospholipase activity in cells. This work provides direct evidence that PLCγ1 is inhibited through obstruction of its membrane-binding surfaces by the regulatory region and that activation must shift PLCγ1 to a conformation competent for membrane binding. Knowledge of the critical sites of membrane interaction extends the mechanistic framework for activation, dysregulation, and therapeutic intervention.

PubMed: 35749497
DOI: 10.1126/sciadv.abp9688

実験手法

X-RAY DIFFRACTION (2 Å)