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Abstract
BackgroundA-kinase-anchoring proteins, AKAPs, constitute a family of scaffolds that play an essential role in catalyzing the spatial-temporal, dynamic interactions of protein kinase A, protein kinase C, tyrosine kinases, G-protein-coupled receptors and ion channels. We studied AKAP5 (AKAP79; MW ~47 kDa) and AKAP12 (gravin, SSECKS; MW ~191 kDa) to probe if these AKAP scaffolds oligomerize.ResultsIn gel analysis and sodium-dodecyl sulfate denaturation, AKAP12 behaved with a MW of a homo-dimer. Only in the presence of the chaotropic agent 8 M urea did gel analysis reveal a monomeric form of AKAP12. By separation by steric-exclusion chromatography, AKAP12 migrates with MW of ~840 kDa, suggestive of higher-order complexes such as a tetramer. Interestingly, the N-(1-840) and C-(840-1782) terminal regions of AKAP12 themselves retained the ability to form dimers, suggesting that the structural basis for the dimerization is not restricted to a single "domain" found within the molecule. In either sodium dodecyl sulfate or urea, AKAP5 displayed a relative mobility of a monomer, but by co-immunoprecipitation in native state was shown to oligomerize. When subjected to steric-exclusion chromatography, AKAP5 forms higher-order complexes with MW ~220 kDa, suggestive of tetrameric assemblies.ConclusionBoth AKAP5 and AKAP12 display the capacity to form supermolecular homo-oligomeric structures that likely influence the localization and function of these molecular scaffolds.
Highlights
A-kinase-anchoring proteins, AKAPs, constitute a family of scaffolds that play an essential role in catalyzing the spatial-temporal, dynamic interactions of protein kinase A, protein kinase C, tyrosine kinases, Gprotein-coupled receptors and ion channels
Two AKAPs, AKAP5 and AKAP12, that associate with the prototypic G proteincoupled receptors (GPCR), the b2-adrenergic receptor (b2-AR), have been the focus of intense research [16,18,19,20,21]
AKAP oligomerization adds a new dimension on how members of this class of scaffold molecules operate in cell signaling
Summary
A-kinase-anchoring proteins, AKAPs, constitute a family of scaffolds that play an essential role in catalyzing the spatial-temporal, dynamic interactions of protein kinase A, protein kinase C, tyrosine kinases, Gprotein-coupled receptors and ion channels. AKAPs dock PKA, but act as molecular “tool boxes” that are multivalent and capable of docking other protein kinases (protein kinase C and the tyrosine kinase Src), phosphoprotein phosphatases, such as protein phosphatase 2B (PP2B) [5], cyclic AMP phosphodiesterases (PDE) [6,7,8,9], adaptor molecules [8,9,10,11], ion channels [12,13,14], and members of the superfamily of G proteincoupled receptors (GPCR) [15,16,17]. Two AKAPs, AKAP5 and AKAP12, that associate with the prototypic GPCR, the b2-adrenergic receptor (b2-AR), have been the focus of intense research [16,18,19,20,21] We examine these two members of the class of GPCR-associated AKAPs and explore the extent to which these proteins, whose
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