ROLE OF PHOSDUCINS IN G PROTEIN SIGNALING

Cells process a wide variety of chemical and physical signals using receptors in their plasma membrane that are linked to G proteins. Examples include hormones, neurotransmitters, odorants and light, to name a few. Numerous diseases have been linked to defects in G protein signaling; including heart disease, several forms of cancer, psychological disorders and drug addictions.

In order to develop more effective treatments for G protein-linked diseases, the cellular processes that regulate G protein signaling must be better understood. G protein signals are propagated by an interaction between the hormone-bound receptor and the heterotrimeric G protein. This interaction catalyzes exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G protein α subunit resulting in dissociation of Gα-GTP from the Gβγ subunits. Once separated, both Gα-GTP and Gβγ regulate various effector enzymes and ion channels that control the concentration of important signaling molecules in the cell such as cyclic nucleotides, inositol phosphates, K⁺ and Ca²⁺. These molecules orchestrate the cellular response to the hormone or other stimulus.

One way in which cells control G protein signaling is through the phosducin family of proteins. Phosducins bind with high affinity to Gβγ and block its interaction with Gα or effectors. Consequently, it has been proposed that phosducins regulate G protein signaling pathways. There are two Gβγ-binding members of this gene family: phosducin, which is found in the photoreceptor cells of the retina and is believed to regulate the G protein pathway responsible for vision and phosducin-like protein (PhLP), which is found in all cells and may be a general G protein regulator. Our lab has found that PhLP binds to the cytosolic chaperonin complex (CCT) which participates in the folding of actin, tubulin and many other proteins in the cell. Unlike actin and tubulin, PhLP is not folded by CCT but it acts as a co-chaperone. In fact, we have found that PhLP and CCT work in concert to fold and assemble the Gβγ dimer.  The Gβγ assembly process appears to function by the following mechanism.  First, nascent Gβ binds CCT in its protein folding cavity and is folding into its β-propeller structure typical of WD-40 repeat proteins like Gβ.  PhLP then binds to the Gβ-CCT complex on top of the folding cavity.  If PhLP is phosphorylated by protein kinase CK2 within a series of three consecutive serine residues near its N-terminus (S18-20), then a PhLP-Gβ complex is released from CCT and Gγ rapidly associates with the PhLP-bound Gβ to form the Gβγ dimer.  Once formed, Gβγ associates with Gα and the endoplasmic reticulum or Golgi membrane, resulting in the release of PhLP and the trafficking of the G protein heterotrimer to the plasma membrane.  If PhLP is not phosphorylated, no PhLP-Gβ is released from the PhLP-Gβ-CCT ternary complex and Gβγ assembly is blocked.

This work suggests that PhLP and its phosphorylation by CK2 could be useful therapeutic targets to control Gβγ assembly and thereby treat diseases linked to malfunctions in G protein signaling systems.