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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

Possible therapeutic strategies to target protein–protein interactions (PPIs) in specific AKAP complexes in the heart. (A) Disruption of the AKAP18γ/δ-PLB interaction prevents PLB phosphorylation on Ser16 and dislocation from SERCA2. This inhibits SERCA2 activation and consequently Ca2+ uptake into the sarcoplasmic reticulum (SR). (B) Disruption of the nesprin-1α/mAKAP interaction promotes AKAP/PKA complex dissociation from the perinuclear membrane and might be a strategy to reduce hypertrophy. (C) Disruption of the connexin 43-ezrin interaction could prevent PKA-mediated phosphorylation increasing inter-cardiomyocyte conductivity which could be cardioprotective following myocardial infarction damage.
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Figure 3: Possible therapeutic strategies to target protein–protein interactions (PPIs) in specific AKAP complexes in the heart. (A) Disruption of the AKAP18γ/δ-PLB interaction prevents PLB phosphorylation on Ser16 and dislocation from SERCA2. This inhibits SERCA2 activation and consequently Ca2+ uptake into the sarcoplasmic reticulum (SR). (B) Disruption of the nesprin-1α/mAKAP interaction promotes AKAP/PKA complex dissociation from the perinuclear membrane and might be a strategy to reduce hypertrophy. (C) Disruption of the connexin 43-ezrin interaction could prevent PKA-mediated phosphorylation increasing inter-cardiomyocyte conductivity which could be cardioprotective following myocardial infarction damage.

Mentions: Lygren et al. (2007) found a PKA/AKAP18δ/PLB complex that regulates SR Ca2+-ATPase 2 (SERCA2) in the heart, which was also later shown in human myocardium (Ahmad et al., 2015). The PLB/SERCA2 complex plays a crucial role in calcium homeostasis in cardiomyocytes and is major regulator of cardiac contractility in vivo (Koss and Kranias, 1996). Under normal conditions dephosphorylated PLB inhibits SERCA2 mediated Ca2+-reabsorption into the SR, a process that is critical for relaxation of the cardiomyocytes and refilling of the heart before the next contraction. However, AKAP18δ acts as a scaffold protein forming a complex of AKAP18δ and PKA together with PLB/SERCA. Upon β-adrenergic stimulation, PLB is phosphorylated and inhibition of SERCA2 is released leading to an increase in Ca2+-reuptake into the SR allowing for pacing the heart by facilitating faster relaxation and filling. Inhibition of PLB phosphorylation by targeting this complex with PPI disruptors is thought to be cardioprotective (Lygren and Taskén, 2008). Moreover, the AKAP18δ/PLB complex should be relatively heart specific, thus minimizing potential side effects. The binding between AKAP18δ and PKA has already been targeted, both by peptides and small molecules. Here they used HTS to screen libraries of small molecules which inhibit the binding between AKAP-PKA (Christian et al., 2011). Another possibility would be to disrupt the interaction between other proteins in the complex (Figure 3A), Lygren et al. (2007) also showed that in neonatal cardiac myocytes the displacement of AKAP18δ/PLB by a short peptide (13–20 aa) affects the phosphorylation of PLB on Ser16 and consequently Ca2+- re-uptake into the SR. Also, removal/reduction of AKAP18δ by siRNA injected in adult cardiomyocytes had the same effect.


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

Calejo AI, Taskén K - Front Pharmacol (2015)

Possible therapeutic strategies to target protein–protein interactions (PPIs) in specific AKAP complexes in the heart. (A) Disruption of the AKAP18γ/δ-PLB interaction prevents PLB phosphorylation on Ser16 and dislocation from SERCA2. This inhibits SERCA2 activation and consequently Ca2+ uptake into the sarcoplasmic reticulum (SR). (B) Disruption of the nesprin-1α/mAKAP interaction promotes AKAP/PKA complex dissociation from the perinuclear membrane and might be a strategy to reduce hypertrophy. (C) Disruption of the connexin 43-ezrin interaction could prevent PKA-mediated phosphorylation increasing inter-cardiomyocyte conductivity which could be cardioprotective following myocardial infarction damage.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Possible therapeutic strategies to target protein–protein interactions (PPIs) in specific AKAP complexes in the heart. (A) Disruption of the AKAP18γ/δ-PLB interaction prevents PLB phosphorylation on Ser16 and dislocation from SERCA2. This inhibits SERCA2 activation and consequently Ca2+ uptake into the sarcoplasmic reticulum (SR). (B) Disruption of the nesprin-1α/mAKAP interaction promotes AKAP/PKA complex dissociation from the perinuclear membrane and might be a strategy to reduce hypertrophy. (C) Disruption of the connexin 43-ezrin interaction could prevent PKA-mediated phosphorylation increasing inter-cardiomyocyte conductivity which could be cardioprotective following myocardial infarction damage.
Mentions: Lygren et al. (2007) found a PKA/AKAP18δ/PLB complex that regulates SR Ca2+-ATPase 2 (SERCA2) in the heart, which was also later shown in human myocardium (Ahmad et al., 2015). The PLB/SERCA2 complex plays a crucial role in calcium homeostasis in cardiomyocytes and is major regulator of cardiac contractility in vivo (Koss and Kranias, 1996). Under normal conditions dephosphorylated PLB inhibits SERCA2 mediated Ca2+-reabsorption into the SR, a process that is critical for relaxation of the cardiomyocytes and refilling of the heart before the next contraction. However, AKAP18δ acts as a scaffold protein forming a complex of AKAP18δ and PKA together with PLB/SERCA. Upon β-adrenergic stimulation, PLB is phosphorylated and inhibition of SERCA2 is released leading to an increase in Ca2+-reuptake into the SR allowing for pacing the heart by facilitating faster relaxation and filling. Inhibition of PLB phosphorylation by targeting this complex with PPI disruptors is thought to be cardioprotective (Lygren and Taskén, 2008). Moreover, the AKAP18δ/PLB complex should be relatively heart specific, thus minimizing potential side effects. The binding between AKAP18δ and PKA has already been targeted, both by peptides and small molecules. Here they used HTS to screen libraries of small molecules which inhibit the binding between AKAP-PKA (Christian et al., 2011). Another possibility would be to disrupt the interaction between other proteins in the complex (Figure 3A), Lygren et al. (2007) also showed that in neonatal cardiac myocytes the displacement of AKAP18δ/PLB by a short peptide (13–20 aa) affects the phosphorylation of PLB on Ser16 and consequently Ca2+- re-uptake into the SR. Also, removal/reduction of AKAP18δ by siRNA injected in adult cardiomyocytes had the same effect.

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