G-proteins

The term "G protein" is an abbreviation for "guanosine triphosphate binding protein". G-proteins occupy a key position in signal transduction, which takes place between a receptor (G-protein receptor) and the downstream second messenger systems.

A distinction is made between membrane-bound heterotrimeric G proteins and cytosolic so-called small G proteins.

Heterotrimeric G-proteins consist of 3 subunits (alpha, beta and gamma). The alpha subunit has a GDP/GTP binding domain that determines the activity state

In the inactive form of the G protein, the alpha subunit GDP binds (see figure). The beta and gamma subunits are attached. When the G-protein is activated (via a G-protein-coupled receptor to which a ligand binds), the bound GDP is exchanged for GTP in the alpha subunit (see figure). During this process, the alpha subunit with the bound GTP is separated (dissociated) from the two beta/gamma subunits.

The dissociated beta/gamma subunits do not disintegrate in the cell but form an independent functional unit.

Heterotrimeric G proteins occupy a key position in signal transduction. They are responsible for significant physiological (e.g. vision, smell, blood pressure regulation etc.) and pathophysiological effects (e.g. arterial hypertension). Subfamilies are:

• Gs proteins: cAMP dependent reactions
• Gi proteins: inhibitory G proteins
• Gq proteins: Phospholipase C coupled G proteins

Small (also known as "non-classical" G proteins) G proteins are monomeric, GTP-binding proteins. They consist of only one (monomeric) subunit, which corresponds in structure and function to a G-alpha subunit. > 100 different small G-proteins are known so far. They are divided into 5 families: Ras, Rho, Rab, Sar1/Arf, Ran.

Small G proteins are involved in the regulation of numerous cell functions, such as the regulation of gene expression (Ras and Rho - the variants Hras, Kras and Nras are proto-oncogenes; Vras is an oncogene), the regulation of cytoskeleton/cell motility (Rho), the regulation of vesicle transport (Rab and Sar1/Arf) and the regulation of transport between cytoplasm and nucleus (Ran). Small G proteins have a lower GTPase activity than heterotrimeric G proteins. They are stimulated by a regulatory protein ("GTPase activating protein"). Small G proteins (like heterotrimeric G proteins) change from the inactive, GDP-bound form into an active, GTP-bound form.

About 1/3 of all tumours show ras mutations, which makes the development of membrane-permeable inhibitors an important therapeutic target. It is advantageous that they preferentially attack the GDP-binding (thus the inactive) form of ras and thus stabilise it.