Explain the roles of protein kinase and protein phosphatase in the regulation of

Question

Explain the roles of protein kinase and protein phosphatase in the regulation of signaling pathways involving phosphate-regulated molecular switches. Explain the roles of GAPs and GEFs in the regulation signaling pathways involving GTP-binding proteins. Explain the roles of adenylyl cyclase and cyclic AMP phosphodiesterase in the regulation of cAMP signaling pathways. Explain why, in all three of these examples, prompt inactivation of these signaling molecules is necessary for rapid signaling to occur.

Explanation / Answer

Because protein kinases have profound effects on a cell, their activity is highly regulated. Kinases are turned on or off by phosphorylation (sometimes by the kinase itself - cis-phosphorylation/autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates.

Phosphatases act in opposition to kinases/phosphorylases, which add phosphate groups to proteins. The addition of a phosphate group may activate or de-activate an enzyme (e.g., kinase signalling pathways) or enable a protein-protein interaction to occur (e.g., SH2 domains ); therefore phosphatases are integral to many signal transduction pathways. It should be noted that phosphate addition and removal do not necessarily correspond to enzyme activation or inhibition, and that several enzymes have separate phosphorylation sites for activating or inhibiting functional regulation. CDK, for example, can be either activated or deactivated depending on the specific amino acid residue being phosphorylated. Phosphates are important in signal transduction because they regulate the proteins to which they are attached. To reverse the regulatory effect, the phosphate is removed. This occurs on its own by hydrolysis, or is mediated by protein phosphatases.

While GAPs serve to regulate the G proteins, there is also some level of regulation of the GAPs themselves. Many GAPs have allosteric sites that serve as interfaces with downstream targets of the particular path that they regulate. For example, RGS9-1, the GAP in the photoreceptors from above, interacts with cGMP phosphodiesterase (cGMP PDE), a downstream component of phototransduction in the retina. Upon binding with cGMP PDE, RGS9-1 GAP activity is enhanced. In other words, a downstream target of photoreceptor-induced signaling binds and activates the inhibitor of signaling, GAP. This positive regulatory binding of downstream targets to GAP serves as a negative feedback loop that eventually turns off the signaling that was originally activated. GAPs are regulated by targets of the G protein that they regulate.

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains involved in the activation of small GTPases. Small GTPases act as molecular switches in intracellular signaling pathways and have many downstream targets. The mechanism of GTPase activation varies among different GEFs. However, there are some similarities in how different GEFs alter the conformation of the G protein nucleotide-binding site. GTPases contain two loops called switch 1 and switch 2 that are situated on either side of the bound nucleotide. These regions and the phosphate-binding loop of the GTPase interact with the phosphates of the nucleotide and a coordinating magnesium ion to maintain high affinity binding of the nucleotide. GEF binding induces conformational changes in the P loop and switch regions of the GTPase while the rest of the structure is largely unchanged. The binding of the GEF sterically hinders the magnesium-binding site and interferes with the phosphate-binding region, while the base-binding region remains accessible. When the GEF binds the GTPase, the phosphate groups are released first and the GEF is displaced upon binding of the entering GTP molecule. Though this general scheme is common among GEFs, the specific interactions between the regions of the GTPase and GEF vary among individual proteins.

cAMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase), one of the first few kinases discovered. It has four sub-units two catalytic and two regulatory. cAMP binds to the regulatory sub-units.It causes them to break apart from the catalytic sub-units. The Catalytic sub-units make their way in to the nucleus to influence transcription.Further effects mainly depend on cAMP-dependent protein kinase, which vary based on the type of cell.If cAMP-dependent pathway is not controlled, it can ultimately lead to hyper-proliferation, which may contribute to the development and/or progression of cancer.

Adenyl cyclase catalyzes the conversion of ATP to 3` 5` cyclic AMP .

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