1. Definition
The small G-proteins, or small GTPases, constitute a family of monomeric proteins that, like heterotrimeric G-proteins, function as molecular switches inside cells to regulate such important cellular processes as signal transduction, organization of the cytoskeleton, vesicle transport, and cell growth.
2. Structure and Mechanism
Small G-proteins share a highly conserved structure: a central G-domain that mediates GTP binding and hydrolysis. Important regions include:
- Switch I and Switch II domains: These domains undergo a conformational change upon GTP versus GDP binding and thereby modulate the activity of the protein and its interactions with effector molecules.
- GTP-binding site: in the activated state, it binds to GTP.
- GTPase activity: Its intrinsic activity allows it to hydrolyze GTP into GDP, inactivating itself.
2.1. GTP-GDP Cycle:
- GTP-bound (active state): In this state, the small G-proteins interact, through this form, with the downstream effectors in conducting certain cellular functions.
- GDP-bound (inactive state): No affinity for the effectors.
2.2. Regulatory proteins involved in the cycle:
- Guanine nucleotide exchange factors (GEFs): they catalyze an exchange of GDP for GTP that activates the G-protein.
- GTPase-activating proteins (GAPs): These proteins increase the intrinsic GTPase activity of the small G-proteins, thereby accelerating GTP hydrolysis and inactivation.
- Guanosine nucleotide dissociation inhibitors (GDIs) prevent the dissociation of the GDP, and hence the G-protein remains in the inactive stage.
3. Major Families of Small G-Proteins
3.1. Ras superfamily
- Function: Regulates cell growth, differentiation, and survival
- Key players: Ras, Raf, Ral
- Function: Many cancers are associated with a mutation in the Ras gene that can result in uncontrolled cell proliferation
3.2. Rho Family
- Function: Controls dynamics of actin cytoskeleton, cell motility, and shape
- Key members: Rho, Rac, Cdc42
- Function: Important in processes such as cell migration, wound healing, and cytokinesis
3.3. Rab Family
- Function: It regulates intracellular vesicle trafficking, including vesicle formation, transport, and fusion
- Representative members: Rab5, Rab7, Rab11
- Function: Mediates proper transport of proteins and lipids between cellular compartments
3.4. Arf family
- Function: Iinvolved in vesicle formation and membrane trafficking within the Golgi apparatus and endosomes
- Key members: Arf1, Arf6
- Function: Regulates the recruitment of coat proteins for vesicle budding
3.5. Ran Family
- Function: Nuclear transport, mitotic spindle assembly, and formation of the nuclear envelope
- Lead User: Ran
- Function: Controls the passage of proteins and RNA in and out of the nucleus
4. Cellular Functions
Small G-proteins have been implicated in many cellular processes, such as:
4.1. Signal transduction
Small G-proteins act as intermediaries in signaling pathways, particularly those initiated by receptor tyrosine kinases (RTKs).
4.2. Cytoskeleton Organisation
Members of the Rho family are key regulators of the actin cytoskeleton. These members regulate the formations of different structures like stress fibers, lamellipodia, and filopodia.
4.3. Vesicle transport
Transport is controlled within the cell by the Rab and Arf families. They control vesicle budding, docking, and fusion that result in the correct delivery of cargo between the endoplasmic reticulum, the Golgi apparatus, endosomes, and the plasma membrane.
4.4. Nuclear Transport
The Ran GTPase regulates the active transport of proteins and RNA between within nuclear pores, a process important for gene regulation and cell division.
5. Pathophysiology and Disease Relevance
Small G-proteins are important in many cellular processes, the dysfunction of which leads to a number of diseases, including:
5.1. Cancer:
The most common oncogenic mutations involve the family of Ras GTPases, which trigger unlimited cell proliferation because of the constitutive activation of signaling pathways driven by Ras. This causes an overproduction of growth signals with reduced apoptosis.
5.2. Neurological Disorders:
Dysregulation of Rho GTPase signaling has been implicated in a wide range of neurodevelopment disorders, including mental retardation, which is characterized by disrupted neuronal migration, dendrite formation, and synaptic plasticity.
5.3. Immune Disorders:
Dysregulation of Rab GTPases will affect the course of immunological functions, including antigen presentation and phagocytosis, associated with the defect in the immune system and to chronic infection.