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Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins.

Calejo AI, Taskén K - Front Pharmacol (2015)

Bottom Line: AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways.Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role.Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Centre, University of Oslo Oslo, Norway ; Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital Oslo, Norway.

ABSTRACT
Cyclic AMP is a ubiquitous intracellular second messenger involved in the regulation of a wide variety of cellular processes, a majority of which act through the cAMP - protein kinase A (PKA) signaling pathway and involve PKA phosphorylation of specific substrates. PKA phosphorylation events are typically spatially restricted and temporally well controlled. A-kinase anchoring proteins (AKAPs) directly bind PKA and recruit it to specific subcellular loci targeting the kinase activity toward particular substrates, and thereby provide discrete spatiotemporal control of downstream phosphorylation events. AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways. Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role. Furthermore, development of novel classes of small molecules involved in displacement of AKAP-bound signal molecules is now emerging. Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of an A kinase anchoring protein (AKAP). AKAPs are categorized by four different characteristics. First, an amphipathic α-helical region of the AKAP interacts with D/D-domain of the PKA R-subunit dimer. Second, they target the supramolecular complex to specific subcellular localizations. Third, AKAPs may also hold PKA substrates by direct binding or by targeting in their vicinity. Lastly, AKAPs can also function as signaling scaffolds for other signaling enzymes. In the absence of cAMP, PKA is inactive and its substrates are not phosphorylated, when cAMP levels increase it binds to the R-subunits and the active catalytic subunits are free to phosphorylate their targets.
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Figure 2: Schematic illustration of an A kinase anchoring protein (AKAP). AKAPs are categorized by four different characteristics. First, an amphipathic α-helical region of the AKAP interacts with D/D-domain of the PKA R-subunit dimer. Second, they target the supramolecular complex to specific subcellular localizations. Third, AKAPs may also hold PKA substrates by direct binding or by targeting in their vicinity. Lastly, AKAPs can also function as signaling scaffolds for other signaling enzymes. In the absence of cAMP, PKA is inactive and its substrates are not phosphorylated, when cAMP levels increase it binds to the R-subunits and the active catalytic subunits are free to phosphorylate their targets.

Mentions: The spatial and temporal organization of cAMP/PKA signaling is attained by a carefully tuned balance between local activation of the signal effector and signal termination machinery assembled and targeted by AKAPs. There are more than 50 AKAPs identified, and even though they belong to a structurally diverse family they all share the ability to enable tightly regulated phosphorylation of substrates that are anchored to or localized in the vicinity of AKAPs together with PKA (Tasken and Aandahl, 2004; Wong and Scott, 2004). The four main features that characterize the AKAP complexes formed (Figure 2) are:


Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins.

Calejo AI, Taskén K - Front Pharmacol (2015)

Schematic illustration of an A kinase anchoring protein (AKAP). AKAPs are categorized by four different characteristics. First, an amphipathic α-helical region of the AKAP interacts with D/D-domain of the PKA R-subunit dimer. Second, they target the supramolecular complex to specific subcellular localizations. Third, AKAPs may also hold PKA substrates by direct binding or by targeting in their vicinity. Lastly, AKAPs can also function as signaling scaffolds for other signaling enzymes. In the absence of cAMP, PKA is inactive and its substrates are not phosphorylated, when cAMP levels increase it binds to the R-subunits and the active catalytic subunits are free to phosphorylate their targets.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4562273&req=5

Figure 2: Schematic illustration of an A kinase anchoring protein (AKAP). AKAPs are categorized by four different characteristics. First, an amphipathic α-helical region of the AKAP interacts with D/D-domain of the PKA R-subunit dimer. Second, they target the supramolecular complex to specific subcellular localizations. Third, AKAPs may also hold PKA substrates by direct binding or by targeting in their vicinity. Lastly, AKAPs can also function as signaling scaffolds for other signaling enzymes. In the absence of cAMP, PKA is inactive and its substrates are not phosphorylated, when cAMP levels increase it binds to the R-subunits and the active catalytic subunits are free to phosphorylate their targets.
Mentions: The spatial and temporal organization of cAMP/PKA signaling is attained by a carefully tuned balance between local activation of the signal effector and signal termination machinery assembled and targeted by AKAPs. There are more than 50 AKAPs identified, and even though they belong to a structurally diverse family they all share the ability to enable tightly regulated phosphorylation of substrates that are anchored to or localized in the vicinity of AKAPs together with PKA (Tasken and Aandahl, 2004; Wong and Scott, 2004). The four main features that characterize the AKAP complexes formed (Figure 2) are:

Bottom Line: AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways.Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role.Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Centre, University of Oslo Oslo, Norway ; Centre for Molecular Medicine Norway, Nordic European Molecular Biology Laboratory Partnership, University of Oslo and Oslo University Hospital Oslo, Norway.

ABSTRACT
Cyclic AMP is a ubiquitous intracellular second messenger involved in the regulation of a wide variety of cellular processes, a majority of which act through the cAMP - protein kinase A (PKA) signaling pathway and involve PKA phosphorylation of specific substrates. PKA phosphorylation events are typically spatially restricted and temporally well controlled. A-kinase anchoring proteins (AKAPs) directly bind PKA and recruit it to specific subcellular loci targeting the kinase activity toward particular substrates, and thereby provide discrete spatiotemporal control of downstream phosphorylation events. AKAPs also scaffold other signaling molecules into multi-protein complexes that function as crossroads between different signaling pathways. Targeting AKAP coordinated protein complexes with high-affinity peptidomimetics or small molecules to tease apart distinct protein-protein interactions (PPIs) therefore offers important means to disrupt binding of specific components of the complex to better understand the molecular mechanisms involved in the function of individual signalosomes and their pathophysiological role. Furthermore, development of novel classes of small molecules involved in displacement of AKAP-bound signal molecules is now emerging. Here, we will focus on mechanisms for targeting PPI, disruptors that modulate downstream cAMP signaling and their role, especially in the heart.

No MeSH data available.


Related in: MedlinePlus