Kinetic model of GPCR-G protein interactions reveals allokairic modulation of signaling.
Kinetic model of GPCR-G protein interactions reveals allokairic modulation of signaling.
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DOI：
10.1038/s41467-022-28789-5
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发表时间：
2022-03-08
影响因子：
16.6
通讯作者：
Sivaramakrishnan S
中科院分区：
文献类型：
--
作者：
Culhane KJ;Gupte TM;Madhugiri I;Gadgil CJ;Sivaramakrishnan S
Established models of ternary complex formation between hormone, G protein coupled receptor (GPCR), and G protein assume that all interactions occur under equilibrium conditions. However, recent studies have established that the lifetimes of these interactions are comparable to the duration of hormone activated GPCR signaling. To simulate interactions during such non-equilibrium conditions, we propose a kinetic model wherein the receptor undergoes rate-limiting transitions between two hormone-bound active states. Simulations, using experimentally measured parameters, demonstrate transient states in ternary complex formation, and delineate the phenomenon of GPCR priming, wherein non-cognate G proteins substantially enhance cognate G protein signaling. Our model reveals that kinetic barriers of slow receptor interconversion can be overcome through allokairic modulation, a regulatory mechanism of ternary complex formation and downstream signaling. Experimentally validated kinetic simulations uncover transient enhancement of GPCR ternary complex formation by allokairic effectors.
