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Assembly of allosteric macromolecular switches: lessons from PKA

Key Points

  • Protein kinases are a large family of regulatory enzymes that change multiple processes in cells by addition of inorganic phosphate to other proteins.

  • All eukaryotic protein kinases share a conserved catalytic core that provides effective phosphotransfer from a molecule of ATP to the recipient protein substrate. Despite this similarity, each kinase phosphorylates only its own substrate or a set of substrates. Understanding how this specificity is achieved is a major challenge.

  • Cyclic AMP-dependent kinase (PKA) is one of the most important protein kinases, as it is the major sensor of cAMP in cells. cAMP is an important second messenger that transmits various signals in living cells.

  • PKA has four major isoforms that are very similar at the level of their catalytic domains or cAMP-binding domains. However, these isoforms differ in their function, sensitivity to cAMP and cell localization.

  • Specificity of different PKA isoforms is achieved by assembling similar tertiary structures into different quaternary complexes. Such packing is driven by highly diverse and highly flexible linkers that are located in the regulatory subunits of PKA.

  • A kinase anchoring proteins (AKAPs), a large family of scaffolding proteins, bind PKA quaternary complexes and incorporate them into even bigger macromolecular complexes, which provide specificity of PKA function in space and time.

Abstract

Protein kinases are dynamic molecular switches that have evolved to be only transiently activated. Kinase activity is embedded within a conserved kinase core, which is typically regulated by associated domains, linkers and interacting proteins. Moreover, protein kinases are often tethered to large macromolecular complexes to provide tighter spatiotemporal control. Thus, structural characterization of kinase domains alone is insufficient to explain protein kinase function and regulation in vivo. Recent progress in structural characterization of cyclic AMP-dependent protein kinase (PKA) exemplifies how our knowledge of kinase signalling has evolved by shifting the focus of structural studies from single kinase subunits to macromolecular complexes.

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Figure 1: The catalytic subunit of PKA as a prototype for the protein kinase superfamily.
Figure 2: Assembly of full length tetrameric holoenzymes is isoform specific and involves ordering of the intrinsically disordered linker.
Figure 3: Molecular basis for regulation of PKA by cAMP.
Figure 4: Assembly of tetrameric holoenzymes.
Figure 5: Specific motifs define isoform-specific interfaces between heterodimers.
Figure 6: PKA is anchored to scaffolds that assemble macromolecular complexes and define foci for PKA signalling.

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Acknowledgements

Work in the authors' laboratory is supported by the Howard Hughes Medical Institute and grants from the US National Institutes of Health (NIH) (GM19301, GM34921) and DK54441 to S. S. T.

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Glossary

Phosphodiesterases

(PDEs). A family of proteins that break down cyclic AMP to AMP.

AGC subfamily

A group of about 60 Ser/Thr kinases that share several sequence, structural and functional similarities. The name is derived from three main representatives of this kinase family, namely cyclic AMP-dependent protein kinase (PKA), PKG and PKC.

Cyclic nucleotide-binding domains

(CNB domains). Conserved protein domains that bind a single molecule of cyclic AMP. Binding of cAMP causes a substantial change of the domain tertiary structure, thus providing a sensor for cAMP levels in the solution.

A kinase anchoring proteins

(AKAPs). A diverse family of scaffolding proteins that have a binding site for the dimerization and docking domain in cyclic AMP-dependent protein kinase regulatory subunits.

Cyclin-dependent kinases

(CDKs). Kinases that regulate the cell cycle. They are activated by a cyclin molecule, which is a small protein that is generated inside the nucleus during mitosis.

EPAC

(Exchange protein directly activated by cyclic AMP). A protein that regulates the activity of RAP1, which is an important cellular regulator. EPAC has a crucial role in cell proliferation and survival.

Intrinsically disordered regions

(IDRs). Parts of protein sequences that cannot accept stable secondary or tertiary structures. Disordered regions are very flexible and often serve as binding sites for other proteins.

Small-angle X-ray scattering

(SAXS). Experimental technique that studies scattering of X-rays by proteins in solution (or protein solutions). Scattering profiles in the small angle range (0.1–10 degrees) provide information about general, low-resolution (50–250Å) forms of the protein.

Small-angle neutron scattering

(SANS). Experimental technique that studies scattering of neutron beams by proteins in solution or protein solutions. It is similar to small-angle X-ray scattering (SAXS) but allows the use of isotope labelling of the protein sample, thus enhancing the technique.

Nonsense-mediated mRNA decay

(NMD). A cellular process that controls the correct synthesis of mRNA. It detects nonsense mutations that insert an erroneous stop codon in the mRNA and thus prevents its folding through degradation.

Long-term depression

(LTD). Weakening of the ability of a neuron to transmit a signal. LTD can last for hours or longer and is one of the most fundamental processes in neurophysiology.

Long-term potentiation

(LTP). Strengthening of the ability of a neuron to transmit signal. This form of synaptic plasticity is thought to underlie memory formation and is characterized by synapses using leads for their long-term strengthening. LTP can last for hours or longer.

PDZ domain

Common domain in a family of signalling proteins. It is named after the three first discovered representatives of this family (Postsynaptic density of 95 kDa, Discs large and zonula occludens 1).

Agouti mice

Heterozygous mice that carry a mutation in the gene encoding agouti. This mutation leads to the yellow obese mouse syndrome, which is characterized by obesity, insulin resistance, hyperglycaemia, increased growth and yellow coat colour.

Apparent activation constant

K¬a(cAMP). The concentration of cAMP that is required for 50% activation of cyclic AMP-dependent protein kinase.

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Taylor, S., Ilouz, R., Zhang, P. et al. Assembly of allosteric macromolecular switches: lessons from PKA. Nat Rev Mol Cell Biol 13, 646–658 (2012). https://doi.org/10.1038/nrm3432

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