BIO254:Gprotein

Introduction

The term G protein refers to proteins that bind the nucleotide guanine as guanosine triphosphate (GTP) and guanosine diphosphate (GDP). There are two types of G proteins: heterotrimeric, or large, G proteins and small G proteins. Heterotrimeric G proteins are membrane-associated and, along with G protein-coupled receptors, function primarily in cell signalling and signal transduction. Small GTP-binding proteins function in diverse cellular processes including signal transduction, cytoskeletal reorganization, and vescicle trafficking. The large small G protein superfamily includes the Ras family (signal transduction), the Rho/Rac family (cytoskeleton), the Rab and Sar1/Arf families (vescicle trafficking), and the Ran family (nuclear import/export) (Takai et al., 2001).

A molecular switch

G protein activity is dependent on whether it is binding GTP or GDP. This useful property has led to the appropriation of G proteins by many cellular processes to be used as "molecular switches". G proteins are generally thought to be "active" when binding GTP and "inactive" when binding GDP. The transition from the GTP-bound state to the GDP-bound state depends on the hydrolysis of GTP. This GTPase activity is either completely intrinsic to the G protein or is enhanced by another class of proteins, "GTPase activating proteins" (GAPs). The GDP to GTP transition requires the dissociation of GDP, so that GTP may again bind at the active site. Proteins that mediate this GDP dissociation are known as guanine nucleotide exchange factors (GEFs). Figure 1 schematizes the switch mechanism for the Rho protein (Luo, 2000).

Heterotrimeric G proteins are unique in that they exist as a complex (G_αβγ) in the GDP-bound state but dissociate (into G_α and G_βγ) upon the release of GDP/binding of GTP.

G Protein-Coupled Receptors

Heterotrimeric G proteins associate with 7-transmembrane domain receptors at the cell membrane. The association of the receptor with all three G protein subunits, G_α, G_β, and G_γ requires that GDP is bound to G_α. When the receptor protein is activated with the appropriate ligand, the ligand/receptor complex acts as a GEF, allowing the GDP to dissociate and GTP to bind. The G proteins then dissociate from the receptor and from each other, with only the β- and γ-subunits remaining bound to one another. G_βγ and G_α-GTP may then activate downstream effectors. Figure 2 is a schematic of this dissociation. G_α-GTP is shown activating adenylyl cyclase (modified from Firestein, 2001).

References

1. Takai Y, Sasaki T, Matozaki T. Small GTP-Binding Proteins. Physiol Rev. 81, 153-208 (2001).

2. Luo L. Rho GTPases in neuronal morphogenesis Nat Rev Neurosci. 1, 173-180 (2000).

3. Firestein, S. How the olfactory system makes sense of scents. Nature 413, 211-218 (2001)

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