GTPase

GTPases are a large family of

GTPases function as molecular switches or timers in many fundamental cellular processes.[2]

Examples of these roles include:

• smell and vision.^[2]
• Protein biosynthesis (a.k.a. translation) at the ribosome.
• Regulation of cell differentiation, proliferation, division and movement.
• Translocation of proteins through membranes.
• Transport of
  vesicles within the cell
  , and vesicle-mediated secretion and uptake, through GTPase control of vesicle coat assembly.

GTPases are active when bound to GTP and inactive when bound to GDP.[2]^[3] In the generalized receptor-transducer-effector signaling model of Martin Rodbell, signaling GTPases act as transducers to regulate the activity of effector proteins.^[3] This inactive-active switch is due to conformational changes in the protein distinguishing these two forms, particularly of the "switch" regions that in the active state are able to make protein-protein contacts with partner proteins that alter the function of these effectors.^[1]

Mechanism

Hydrolysis of GTP bound to an (active) G domain-GTPase leads to deactivation of the signaling/timer function of the enzyme.

Some GTPases also bind to accessory proteins called guanine nucleotide dissociation inhibitors or GDIs that stabilize the inactive, GDP-bound state.^[6]

The amount of active GTPase can be changed in several ways:

1. Acceleration of GDP dissociation by GEFs speeds up the accumulation of active GTPase.
2. Inhibition of GDP dissociation by guanine nucleotide dissociation inhibitors (GDIs) slows down accumulation of active GTPase.
3. Acceleration of GTP hydrolysis by GAPs reduces the amount of active GTPase.
4. Artificial GTP analogues like GTP-γ-S, β,γ-methylene-GTP, and β,γ-imino-GTP that cannot be hydrolyzed can lock the GTPase in its active state.
5. Mutations (such as those that reduce the intrinsic GTP hydrolysis rate) can lock the GTPase in the active state, and such mutations in the small GTPase Ras are particularly common in some forms of cancer.^[7]

G domain GTPases

In most GTPases, the specificity for the base guanine versus other nucleotides is imparted by the base-recognition motif, which has the consensus sequence [N/T]KXD. The following classification is based on shared features; some examples have mutations in the base-recognition motif that shift their substrate specificity, most commonly to ATP.^[8]

TRAFAC class

The TRAFAC class of G domain proteins is named after the prototypical member, the translation factor G proteins. They play roles in translation, signal transduction, and cell motility.^[8]

Translation factor superfamily

Multiple classical

The superfamily also includes the Bms1 family from yeast.[8]

Ras-like superfamily

Heterotrimeric G proteins

G protein signaling is terminated by hydrolysis of bound GTP to bound GDP.[2]^[3] This can occur through the intrinsic GTPase activity of the α subunit, or be accelerated by separate regulatory proteins that act as GTPase-activating proteins (GAPs), such as members of the Regulator of G protein signaling (RGS) family).^[4] The speed of the hydrolysis reaction works as an internal clock limiting the length of the signal. Once G_α is returned to being GDP bound, the two parts of the heterotrimer re-associate to the original, inactive state.^[2][3]

The heterotrimeric G proteins can be classified by sequence homology of the α unit and by their functional targets into four families: G_s family, G_i family, G_q family and G₁₂ family.^[12] Each of these G_α protein families contains multiple members, such that the mammals have 16 distinct _α-subunit genes.^[12] The G_β and G_γ are likewise composed of many members, increasing heterotrimer structural and functional diversity.^[12] Among the target molecules of the specific G proteins are the second messenger-generating enzymes adenylyl cyclase and phospholipase C, as well as various ion channels.^[16]

Small GTPases

This class is defined by loss of two beta-strands and additional N-terminal strands. Both namesakes of this superfamily, myosin and kinesin, have shifted to use ATP.^[8]

Large GTPases

See dynamin as a prototype for large monomeric GTPases.

SIMIBI class

Much of the SIMIBI class of GTPases is activated by dimerization.^[8] Named after the signal recognition particle (SRP), MinD, and BioD, the class is involved in protein localization, chromosome partitioning, and membrane transport. Several members of this class, including MinD and Get3, has shifted in substrate specificity to become ATPases.^[19]

Translocation factors

This section is missing information about FlhF, which is not involved in the SRP at all but has a similar structure to Ffh and FtsY. Please expand the section to include this information. Further details may exist on the talk page. (October 2021)

For a discussion of

While tubulin and related structural proteins also bind and hydrolyze GTP as part of their function to form intracellular tubules, these proteins utilize a distinct tubulin domain that is unrelated to the G domain used by signaling GTPases.^[20]

There are also GTP-hydrolyzing proteins that use a

• G protein-coupled receptors
• Growth factor receptor
• Septins

References