Abstract

This chapter focuses on the structurally conserved regulatory (R) subunit anchoring domain and deals with the examples of unique subcellular targeting domains that localize anchored-protein kinase (PKA) for regulation of co-localized target substrates. There are three PKA C subunit isoforms (Cαβγ, Cβ, Cγ) and four R subunit isoforms (RIα, RIβ, RIIα, RIIβ). NMR structural studies show that both the RI and RII N-terminal dimerization domains form anti-parallel four-helix bundles in which dimerization creates an extended hydrophobic surface that binds the A-kinase anchoring proteins (AKAP). The AKAPs all bind to the R subunit N-terminal dimerization domain through hydrophobic interactions. The PKA anchoring domains from different AKAPs have very little primary amino acid sequence similarity yet share a conserved hydrophobic character and secondary structure. Thus, AKAPs are a family of functionally related proteins arising from convergent evolution, as opposed to diverging from a common ancestral AKAP protein. The common hydrophobic and secondary structure in AKAP PKA anchoring domains is seen as a conserved spacing of hydrophobic residues, which map to one side of an amphipathic α-helix of about 18 residues in length. AKAP molecules have been characterized at a myriad of distinct subcellular locations including the plasma membrane, intracellular vesicles, actin and microtubule cytoskeletons, mitochondria, endoplasmic reticulum (ER), Golgi, and centrosomes. The AKAP protein MAP2 is targeted to dendritic microtubules in neurons by direct binding to tubulin. Scar/Wave1, an AKAP that also anchors the abl-Tyrosine kinase, binds to actin both in focal adhesions and membrane ruffles in fibroblasts where it regulates the actin polymerization activity of the Arp2/3 complex.

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