The correlation between multidomain enzymes and multiple activation mechanisms--the case of phospholipase Cβ and its...

Phospholipase Cβ2 (PLCβ2) is a large, multidomain enzyme that catalyzes the hydrolysis of the signaling lipid phosphoinositol 4,5 bisphosphate (PIP2) to promote mitogenic and proliferative changes in the cell. PLCβ2 is activated by Gα and Gβγ subunits of heterotrimeric G proteins, as well as small G proteins and specific peptides. Activation depends on the nature of the membrane surface. Recent crystal structures suggest one model of activation involving the movement of a small autoinhibitory loop upon membrane binding of the enzyme. Additionally, solution studies indicate multiple levels of activation that involve changes in the membrane orientation as well as interdomain movement. Here, we review the wealth of biochemical studies of PLCβ2-G protein activation and propose a comprehensive model that accounts for both the crystallographic and solution results.