Advanced Molecular Genetics-Biology 566 G Proteins
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G-proteins

G proteins are often called GTP-binding proteins and are all GTPases.

G proteins are a class of GTP-binding proteins that interact with 7TM receptors and are composed of three subunits, a, b, g.

Binding of a hormone to the 7TM receptor induces a conformational change that activates the G-protein complex and facilitates the exchange of GTP for GDP on the a subunit.

The a G-protein subunit then separates from the b/g subunits and either the a or the b/g complex activates downstream activity in the signal transduction pathway.

The a and b/g subunits are tethered to the plasma membrane through covalently attached fatty acid sidechains. The a is anchored at the N-terminus and the g at the C-terminus. The b/g are tightly associated.

Hydrolysis of the GTP to GDP by the a subunit allows the a, b, g complex to reform and ends stimulation of downstream effector pathway elements.

GTP hydrolysis is accelerated upon contact with effector protein.

Regulators of G-Protein Signalling proteins (RGS) accelerate the rate of GTP hydrolysis and act as regulators.

The diversity of G-protein components is mainly due to the alpha subunit. In animals there are 16 alpha subunit genes and with alternative splicing there are 20 different subunits.

There are 5 beta subtypes of G-proteins sharing 50-90% identity and at least 12 subtypes of gamma, whose sequences are more diverse.

Beta/gamma seem to be interchangeable in their association with alpha subunits with some exceptions. Activated beta/gamma subunits have been found to activate K+ channels.

The activated beta/gamma subunits also serve to present negative feedback signals through the binding of the bark protein which is a kinase that phosphorylates the receptor and desensitizes it

Monomeric GTP-binding proteins

There are over 70 known monomeric GTPases. Several of them are related to Ras.

Ras proteins are often referred to as proto-oncogene products because derivatives have been found to induce sarcomas and has been associated with a high proportion of human tumors.

Ras proteins are modified at their C-terminus by the addition of a lipid group which tethers the protein to the plasma membrane.

"Ras lies at the center of a network of interacting pathways and is nodulated directly and indirectly by several receptors and, in turn, has its influence on a large number of downstream processes."