GTPase
GTPases are a large family of
Functions
GTPases function as molecular switches or timers in many fundamental cellular processes.[2]
Examples of these roles include:
- 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.
GTPase activity serves as the shutoff mechanism for the signaling roles of GTPases by returning the active, GTP-bound protein to the inactive, GDP-bound state.
To become activated, GTPases must bind to GTP. Since mechanisms to convert bound GDP directly into GTP are unknown, the inactive GTPases are induced to release bound GDP by the action of distinct regulatory proteins called
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:
- Acceleration of GDP dissociation by GEFs speeds up the accumulation of active GTPase.
- Inhibition of GDP dissociation by guanine nucleotide dissociation inhibitors (GDIs) slows down accumulation of active GTPase.
- Acceleration of GTP hydrolysis by GAPs reduces the amount of active GTPase.
- 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.
- 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
Heterotrimeric G proteins act as the transducers of
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 Gα 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: Gs family, Gi family, Gq family and G12 family.[12] Each of these Gα protein families contains multiple members, such that the mammals have 16 distinct α-subunit genes.[12] The Gβ and Gγ 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
Myosin-kinesin superfamily
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.(October 2021) |
For a discussion of
Other GTPases
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
See also
- G protein-coupled receptors
- Growth factor receptor
- Septins
References
- ^ PMID 8462668.
- ^ PMID 3113327.
- ^ S2CID 11025853.
- ^ PMID 9430654.
- PMID 3086320.
- PMID 9588168.
- S2CID 195761467.
- ^ PMID 11916378.
- S2CID 1388090.
- PMID 29235176.
- PMID 17214893.
- ^ PMID 10819326.
- PMID 9131251.
- PMID 11313912.
- S2CID 23659116.
- S2CID 20136388.
- ^ PMID 11152757.
- PMID 2116664.
- PMID 27658684.
- S2CID 5945125.
External links
- GTPase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- MBInfo - RhoGTPases Archived 2013-03-31 at the Wayback Machine