Evolution of the eukaryotic protein kinases as dynamic molecular switches.
Protein kinases have evolved in eukaryotes to be highly dynamic molecular switches that regulate a plethora of biological processes. Two motifs, a dynamic activation segment and a GHI helical subdomain, distinguish the eukaryotic protein kinases (EPKs) from the more primitive eukaryotic-like kinases. The EPKs are themselves highly regulated, typically by phosphorylation, and this allows them to be rapidly turned on and off. The EPKs have a novel hydrophobic architecture that is typically regulated by the dynamic assembly of two hydrophobic spines that is usually mediated by the phosphorylation of an activation loop phosphate. Cyclic AMP-dependent protein kinase (protein kinase A (PKA)) is used as a prototype to exemplify these features of the PKA superfamily. Specificity in PKA signalling is achieved in large part by packaging the enzyme as inactive tetrameric holoenzymes with regulatory subunits that then are localized to macromolecular complexes in close proximity to dedicated substrates by targeting scaffold proteins. In this way, the cell creates discrete foci that most likely represent the physiological environment for cyclic AMP-mediated signalling.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA. staylor@ucsd.edu
Susan S
SS
Taylor
Malik M
MM
Keshwani
Jon M
JM
Steichen
Alexandr P
AP
Kornev
D000494:Allosteric Regulation; D020134:Catalytic Domain; D004789:Enzyme Activation; D004795:Enzyme Stability; D056890:Eukaryota / Q000737:chemistry / Q000201:enzymology*; D019143:Evolution, Molecular; D020035:Holoenzymes / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D010766:Phosphorylation; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry*; D015398:Signal Transduction; D013379:Substrate Specificity
D020035:Holoenzymes; D011494:Protein Kinases