Phosphorylase kinase: the complexity of its regulation is reflected in the complexity of its structure.
Intracellular glycogen stores are used to maintain blood-glucose homeostasis during fasting, are a source of energy for muscle contraction, and are used to support a broad range of cellular activities in most tissues. A diversity of signals accelerate glycogen degradation that are mediated by phosphorylase b kinase (Phk), which phosphorylates and thereby activates glycogen phosphorylase. Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. Ca2+ relieves inhibition via the delta subunit, which is identical to calmodulin but remains an integral component of the holoenzyme even when the [Ca2+] is lowered to nanomolar levels. Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. The stimulatory effects of Ca2+ and phosphorylation appear to be structurally coupled and are cooperative. In addition, Phk is activated in vitro by autophosphorylation, limited proteolysis of the regulatory subunits, and various allosteric effectors and these may also be mechanisms of physiological importance. The molecular mechanisms of regulation are currently poorly understood, but new insights are beginning to emerge. This review discusses current knowledge and concepts of the structure, function and regulation of Phk.
Brushia
R J
RJ
Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., MS1-260, Berkeley, CA 94720, USA.
Walsh
D A
DA
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000502:physiology; D016384:Consensus Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010764:Phosphorylase Kinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D020035:Holoenzymes; D007527:Isoenzymes; D010764:Phosphorylase Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium