Trends in Cell Biology
ReviewAKAPs: from structure to function
Section snippets
cAMP signalling pathways and AKAPs
One of the best-understood signal-transduction pathways involves the second-messenger cAMP2. cAMP is generated following receptor activation by many different hormones and neurotransmitters, leading to the activation of PKA. Many, if not all, of the components of this signalling cascade – receptors, heterotrimeric G proteins, adenylyl cyclases and kinase subunits – have been cloned and characterized. The PKA holoenzyme consists of two catalytic subunits (C) and a regulatory subunit (R) dimer.
Structural determinants of AKAP–RII interaction
Early on, deletion-mapping studies identified a region of MAP2 that mediated association with RII16, 17. Subsequent computer-aided secondary-structural analysis predicted that sequences of 14–18 residues in MAP2 and other AKAPs have a high probability of amphipathic helix formation, with hydrophobic residues aligned along one face of the helix and charged residues along the other18. The human thyroid anchoring protein Ht31 served as a prototype to test this model. Indeed, introduction of amino
Targeting regions
A property unique to each AKAP is a targeting sequence that determines the location of the protein in the cell. This is demonstrated in Fig. 2 by a montage of some compartment-specific AKAPs. A combination of subcellular-fractionation and immunohistochemical studies have identified AKAPs in association with a variety of cellular compartments, including centrosomes, dendrites, endoplasmic reticulum, mitochondria, nuclear membrane, plasma membrane and vesicles (Table 1). Although the subcellular
AKAPs as multivalent anchoring proteins
Although AKAPs have been defined on the basis of their interaction with PKA, an additional feature of many of these molecules is their ability to bind to other signalling enzymes. By simultaneously binding enzymes with opposing actions, such as kinases and phosphatases, these multivalent anchoring proteins could target entire signalling complexes to specific substrates (Fig. 3). For example, AKAP79 binds to PKA, protein kinase C (PKC) and the protein phosphatase calcineurin (PP2B)31, 32 (Fig. 3a
Functional consequences of PKA anchoring
The biological relevance of anchoring is underscored by recent functional studies that use AKAPs as reagents to manipulate the subcellular distribution of PKA. To date, two approaches have been exploited: cellular disruption of PKA anchoring using inhibitor peptides and protein fragments derived from Ht31, and expression of compartment-specific AKAPs to redistribute the kinase to defined subcellular sites. Many of these studies have focused on rapid cAMP-responsive events, such as modulation of
Conclusions and perspectives
In the past few years, multiple lines of evidence have suggested that AKAPs are important in the organization of cAMP-mediated signalling events. The anchoring protein serves at least two functions: to place the PKA holoenzyme at locations where it can respond rapidly to the ebb and flow of cAMP production and to favour certain PKA phosphorylation events by placing the enzyme close to a particular subset of substrates. This latter point has been highlighted by a series of recent functional
Acknowledgements
We thank our colleagues in the Scott lab for their critical and insightful comments on the manuscript and James Goldenring (Medical College of Georgia) for providing a manuscript prior to publication. We also thank Susan Taylor (UCSD) and Patricia Jennings (UCSD) for providing artwork. This work was supported in part by DK 44239 to J. D. S.
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