GTPase

Functions

GTPases play an important role in:

• transmembrane receptors, including recognition of taste, smell and light.
• ribosome.
• Control and differentiation during cell division.
• Translocation of proteins through membranes.
• Transport of vesicles within the cell. (GTPases control assembly of vesicle coats).

Mechanism

The hydrolysis of the γ ion Mg²⁺.

Major Motifs

In most GTPases, the specificity for the base guanine is imparted by the base-recognition motif, which has the consensus sequence [N/T]KXD. ^[1]

Regulatory GTPases

Regulatory GTPases, also called the biochemical processes. Most prominent among the regulatory GTPases are the G proteins.

GTP switch

All regulatory GTPases have a common mechanism that enables them to switch a Guanine nucleotide exchange factors (GEFs), which cause the GDP to dissociate from the GTPase, leading to its association with a new GTP. This closes the cycle to the active state of the GTPase; the irreversible hydrolysis of the GTP to GDP forces the cycle to run only in one direction. Only the active state of the GTPase can transduce a signal to a reaction chain.

Switch regulation

The efficiency of the signal transduction via a GTPase depends on the ratio of active to inactive GTPase. That equals:

with k_diss.GDP being the dissociation constant of GDP, and k_cat.GTP the hydrolysis constant of GTP for the specific GTPase. Both constants can be modified by special regulatory proteins.
The amount of active GTPase can be changed in several ways :

1. Acceleration of GDP dissociation by GEFs speeds up the building of active GTPase.
2. Inhibition of GDP dissociation by guanine nucleotide dissociation inhibitors (GDIs) slows down the building of active GTPase.
3. Acceleration of GTP hydrolysis by GAPs reduces the amount of active GTPase.
4. GTP analogues like γ-S-GTP, β,γ-methylene-GTP, and β,γ-imino-GTP that cannot be hydrolized fixate the GTPase in its active state.

Heterotrimeric G proteins

These G proteins are made from three subunits, with the G domain located on the largest one (the α unit); together with the two smaller subunits (β and γ units), they form a tightly associated protein complex. α and γ unit are associated with the membrane by lipid anchors. Heterotrimeric G proteins act as the specific reaction partners of ion channels. The heterotrimeric G proteins can be classified by sequence homology of the α unit into four families:

1. G_s family. These G proteins are used in the signal transduction of taste and smell. They always use the activation of cholera toxin, which is the cause of the fatal effects of infection with Vibrio cholerae.
2. G_i family. The i stands for inhibition of the pertussis toxin of Bordetella pertussis.
3. G_q family. These proteins usually have phospholipase C as effector protein.
4. G₁₂ family. These G proteins can be activated by thromboxan receptors and thrombin receptors. Their effector proteins are unknown.

By combination of different α, β and γ subunits, a great variety (>1000) G proteins can be produced. GDP is not needed for GTP.

Activation cycle of heterotrimeric G proteins

In the basic state, the G_α-GDP-G_βγ complex and the receptor that can activate it are separately associated with the membrane. On receptor activation, the receptor becomes highly affine for the G protein - GDP complex. On binding with the complex, GDP dissociates from the complex; the receptor works as a GEF - GDP-GTP Exchange Factor; the free complex has a high affinity for GTP. Upon GTP binding, both G_α-GTP and G_βγ separate from both the receptor and from each other. Depending on the lifetime of the active state of the receptor, it can activate more G proteins this way.
Both G_α-GTP and G_βγ can now activate separate and/or the same effector molecules, thus sending the signal further down the signal reaction chain. Once the intrinsic GTPase activity of the α unit has hydrolyzed the GTP to GDP, and then the two parts are disassociated to the original, inactive state. The speed of the hydrolysis reaction works as an internal clock for the length of the signal.

The Ras GTPase superfamily

These are small monomeric proteins homologous to Arf and Ran.

Translation factor family

These GTPases play an important role in initiation, elongation and termination of protein biosynthesis.

Translocation factors

See signal recognition particle (SRP).

Large GTPases

See dynamin as a prototype for large GTPases.

See also

• G protein-coupled receptors
• Rho-kinase

References

v • d • e ATPase
3.6.5	GTPase

v • d • e Acid anhydride hydrolases: GTPases/Dynamin (is a GTPase, is not a G protein) - Tubulin