title: Spatial Organization in Protein Kinase A Signaling Emerged at the Base of Animal Evolution.
abstract: In phosphorylation-directed signaling, spatial and temporal control is organized by complex interaction networks that diligently direct kinases toward distinct substrates to fine-tune specificity. How these protein networks originate and evolve into complex regulatory machineries are among the most fascinating research questions in biology. Here, spatiotemporal signaling is investigated by tracing the evolutionary dynamics of each functional domain of cAMP-dependent protein kinase (PKA) and its diverse set of A-kinase anchoring proteins (AKAPs). Homologues of the catalytic (PKA-C) and regulatory (PKA-R) domains of the (PKA-R)2-(PKA-C)2 holoenzyme were found throughout evolution. Most variation was observed in the RIIa of PKA-R, crucial for dimerization and docking to AKAPs. The RIIa domain was not observed in all PKA-R homologues. In the fungi and distinct protist lineages, the RIIa domain emerges within PKA-R, but it displays large sequence variation. These organisms do not harbor homologues of AKAPs, suggesting that efficient docking to direct spatiotemporal PKA activity evolved in multicellular eukaryotes. To test this in silico hypothesis, we experimentally screened organisms with increasing complexity by cAMP-based chemical proteomics to reveal that the occurrence of PKA-AKAP interactions indeed coincided and expanded within vertebrates, suggesting a crucial role for AKAPs in the advent of metazoan multicellularity.
authors.affiliation: †Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.|‡Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, The Netherlands.|∥Department of Toxicogenomics, Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Mao
authors.initials: M
authors.lastname: Peng
authors.affiliation: †Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.|‡Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Thin Thin
authors.initials: TT
authors.lastname: Aye
authors.affiliation: §Theoretical Biology and Bioinformatics, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Berend
authors.initials: B
authors.lastname: Snel
authors.affiliation: †Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.|‡Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: van Breukelen
authors.affiliation: †Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.|‡Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Scholten
authors.affiliation: †Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.|‡Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D020134:Catalytic Domain; D017124:Conserved Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010802:Phylogeny; D040901:Proteomics; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000201:enzymology
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases
keywords: AKAP; PKA; RIIa; evolution; proteomics