GTP Binding Proteins

Trimeric G Proteins

The trimeric G-proteins (GTP binding proteins) play a pivotal role in the signal transduction pathways for numerous hormones and neurotransmitters. The three subunits of the protein are labelled alpha, beta, and gamma. Both the alpha and gamma subunits are bound to the membrane via attached lipid molecules (related to fatty acids and cholesterol). The receptors are proteins with seven transmembrane alpha-helices.

View this ANIMATION to see the sequence of events during the activation of a receptor coupled to a trimeric G protein.

The binding of the hormone or neurotransmitter to the receptor causes GTP to replace GDP on the alpha subunit. As a result, the alpha subunit dissociates from the other two.

Subsequently, the alpha subunit and the combined beta and gamma subunits move along the inner surface of the membrane to specific ion channels or membrane enzymes. Ion channels opened in this way are often potassium channels; an example of a membrane enzyme with this type of activation is adenylyl cyclase. Note, however, that in some cases the G protein has an inhibitory rather than stimulatory effect.

The sequence ends when the alpha subunit hydrolyzes the GTP to GDP, allowing the subunits associate again.

The animation shows the alpha subunit opening an ion channel while the combined beta and gamma subunits are shown activating a membrane enzyme. However, the diagram just as easily could have been drawn the other way around. Both the alpha subunit and the combined beta and gamma subunits potentially can activate a variety of ion channels or membrane enzymes.

The animation also shows just one ion channel or membrane enzyme being activated. Actually, numerous individual ion channels or membrane enzymes would be activated, because a receptor with a regulatory molecule bound can activate multiple G-proteins. Thus, this step in the signal transduction pathway amplifies the response.

(For clarity, the subunits are shown in a row. Actually, the points at which the alpha subunit and the gamma subunit are attached to the membrane are fairly close together.)

Receptors with Seven Transmembrane Domains

As mentioned above, the receptors coupled to trimeric G proteins belong to a class of widespread and important membrane proteins. These are the seven transmembrane domain receptors. The epinephrine receptor shown to the right illustrates the most important receptor with this characteristic structure.

The binding of epinephrine or any related agonist to the indicated extracellular region activates the receptor. Once this happens, the receptor in turn causes a trimeric G protein on the inside of the membrane to dissociate into the alpha subunit and the beta/gamma subunits. As described above, these two structures move along under the surface of the membrane and activate membrane enyzmes or ion channels.

QUESTION: What is the role of the bARK indicated in the figure above? (from lecture)

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Monomeric G Proteins

Ras proteins are monomeric G-proteins of widespread importance. But ras proteins tend to be central in transduction pathways linked to growth and development, rather than in the responses of cells to hormones and neurotransmitters. Thus, the regulatory molecules here tend to be growth factors.

Each receptor molecule has only one transmembrane alpha helix. However, the binding of the growth factor creates a dimer from two of the receptor molecules. This allows the tyrosine kinase activity of each molecule of the dimer to phosphorylate the other. Once this happens, an adaptor protein binds and recruits a guanine nucleotide exchange protein to the membrane. This protein in turn causes GTP to replace GDP on the ras protein.

The ras protein with GTP bound can now activate a protein kinase cascade, which ultimately leads to the phosphorylation of transcription factors in the nucleus, which in turn alter gene expression.

View this ANIMATION to see the sequence of events during the activation of a ras protein.

Quick Quiz

Fill in Answer Correct False Correct Answer
What protein, in the discussion above, is a monomeric GTP binding protein?
What happens to the intracellular domains of the growth factor receptor following the binding of the growth factor?
What type of protein in the RAS signalling pathway is phosphorylated in the nucleus and binds to DNA?
How many polypeptide chains (subunits) are there in the complete receptor for the growth factor?

(Spelling must be correct)
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