GTPases

GTPases

GTPases are a large family of hydrolase enzymes that bind and hydrolyze guanosine triphosphate (GTP). They play a critical role in various cellular processes, including signal transduction, protein synthesis, cell division, and intracellular transport. GTPases act as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state.

Structure and Function

GTPases are characterized by their ability to bind guanine nucleotides and possess intrinsic GTPase activity, which allows them to hydrolyze GTP to GDP. This hydrolysis reaction is crucial for their function as molecular switches. The transition between the GTP-bound and GDP-bound states is often regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs).

GTPase Superfamily

The GTPase superfamily is divided into several subfamilies, each with distinct functions:

• Ras superfamily: Involved in signal transduction pathways. Members include Ras, Rho, and Rab proteins.
• Heterotrimeric G proteins: Composed of α, β, and γ subunits, these proteins are involved in transmitting signals from G protein-coupled receptors (GPCRs).
• Dynamin-related proteins: Involved in membrane fission and fusion events.
• Translation factors: Such as EF-Tu and EF-G, which are involved in protein synthesis.

Mechanism of Action

GTPases function by cycling between an active and inactive state:

1. **GTP Binding**: In the active state, GTPases bind GTP, which induces a conformational change that allows them to interact with target proteins.
2. **Signal Transmission**: The active GTP-bound form interacts with downstream effectors to propagate cellular signals.
3. **GTP Hydrolysis**: The intrinsic GTPase activity hydrolyzes GTP to GDP, leading to a conformational change to the inactive state.
4. **GDP Release**: GEFs facilitate the release of GDP, allowing GTP to bind and reactivate the GTPase.

Biological Roles

GTPases are involved in a wide range of cellular processes:

• **Signal Transduction**: Ras proteins are key regulators of cell growth and differentiation.
• **Cytoskeletal Dynamics**: Rho family GTPases regulate the actin cytoskeleton, affecting cell shape and motility.
• **Vesicular Transport**: Rab GTPases are essential for vesicle trafficking in the secretory and endocytic pathways.
• **Protein Synthesis**: Translation factors like EF-Tu and EF-G are critical for the elongation phase of protein synthesis.

Clinical Significance

Mutations in GTPase genes can lead to various diseases, including cancer, due to their role in regulating cell proliferation and survival. For example, mutations in the Ras gene are common in many types of cancer, making it a target for therapeutic intervention.

See Also

• Enzyme
• Signal transduction
• Protein synthesis

References

• Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular Biology of the Cell. Garland Science.
• Vetter, I. R., & Wittinghofer, A. (2001). The guanine nucleotide-binding switch in three dimensions. Science, 294(5545), 1299-1304.