Phosphorylase kinase

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Phosphorylase kinase
PhK 1QL6 gamma small.png
Catalytic (gamma) subunit of phosphorylase kinase
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EC no. 2.7.11.19
CAS no. 9001-88-1
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Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformational shift which favors the more active glycogen phosphorylase “a” form over the less active glycogen phosphorylase b. [1]

Contents

The protein is a hexadecameric holoenzyme—that is, a homotetramer in which each subunit is itself a tetramer—arranged in an approximate “butterfly” shape. Each of the subunits is composed of an α, β, γ and δ subunit. The γ subunit is the site of the enzyme's catalytic activity while the other three subunits serve regulatory functions.

When unmodified, the α and β subunits inhibit the enzyme's catalysis, but phosphorylation of both these subunits by protein kinase A (PKA, or cAMP-dependent protein kinase) reduces their respective inhibitory activities. The δ subunit is the ubiquitous eukaryotic protein calmodulin which itself has 4 calcium ion binding sites. When cytosolic Ca2+ levels rise-to as low as 10−7 M—the δ subunit undergoes a large conformational change that activates the kinase's activity by binding to a complementary hydrophobic patch on the catalytic γ subunit. [2]

Genes

History

Phosphorylase kinase was the first protein kinase to be isolated and characterized in detail, accomplished first by Krebs, Graves and Fischer in the 1950s. [3] [4] [5] At the time, the scientific community was largely unaware of the importance of protein phosphorylation in the regulation of cellular processes, and many in the field dismissed phosphoproteins as biologically unimportant. Since covalent modification by phosphorylation is a widespread, important method of biochemical regulation in a wide variety of cellular processes, the discovery of this reaction has had enormous impact on scientific understanding of regulatory mechanisms.

The substrate of PhK, glycogen phosphorylase, had been isolated by Carl and Gerty Cori in the 1930s, who determined that there were two forms: an inactive form b and an active form a. However, for unknown reasons at the time, the only way to isolate glycogen phosphorylase a from muscle tissue was by paper filtration – other methods, such as centrifugation, would not work. It was a critical insight on the part of Fischer et al. that it was the presence of calcium ions in the filter paper that was generating the active “a” isoform. Later research revealed that the calcium ions were in fact activating phosphorylase kinase via the δ regulatory subunit, leading to the phosphorylation of glycogen phosphorylase. [6] [7] [8]

Mechanism

The precise details of the PhK’s catalytic mechanism are still under study. [9] [10] [11] [12] [13] While this may seem surprising given that it was isolated over 50 years ago, there are significant difficulties in studying the finer details of PhK’s structure and mechanism due to its large size and high degree of complexity. [2] In the active site, there is significant homology between PhK and other so-called P-loop protein kinases such as protein kinase A (PKA, cAMP-dependent kinase). In contrast to these other proteins, which typically require phosphorylation of a serine or tyrosine residue in the catalytic site to be active, the catalytic γ subunit of PhK is constitutively active due to the presence of a negatively charged glutamate residue, Glu-182. [11] [12]

Structural and biochemical data suggest one possible mechanism of action for the phosphorylation of glycogen phosphorylase by PhK involves the direct transfer of phosphate from adenosine triphosphate (ATP) to the substrate serine. [9]

Structure

Phosphorylase kinase is a 1.3 MDa hexadecameric holoenzyme, though its size can vary somewhat due to substitution of different subunit isoforms via mRNA splicing. [14] [15] [16] It consists of four homotetramers each comprised four subunits (α,β,δ,γ). Only the γ subunit is known to possess catalytic activity, while the others serve regulatory functions. Due to the instability of the regulatory subunits in solution, only the γ subunit has been crystallized individually:

Overall, the subunits are arranged in two lobes oriented back-to-back in what has been described as a “butterfly” shape with D2 symmetry. [14] [17] [18] Each lobe consists of two tetramers, each consisting of the αβδγ subunits as described earlier. The δ subunit is indistinguishable from cellular calmodulin, while the α and β subunits are close homologues of each other which are proposed to have arisen by gene duplication and subsequent differentiation. [19]

Biological function and regulation

Overview of phosphorylase kinase regulation. PhK diagram.png
Overview of phosphorylase kinase regulation.

Physiologically, phosphorylase kinase plays the important role of stimulating glycogen breakdown into free glucose-1-phosphate by phosphorylating glycogen phosphorylase and stabilizing its active conformation. This activity is particularly important in liver and muscle cells, though for somewhat different purposes. While muscle cells generally break down glycogen to power their immediate activity, liver cells are responsible for maintaining glucose concentration in the bloodstream. Thus, the regulatory mechanisms of PhK activity vary somewhat depending on cell type. [1]

In general, the enzyme is regulated allosterically and by reversible phosphorylation. Hormones, nerve impulses and muscle contraction stimulate the release of calcium ions. These act as an allosteric activator, binding to the δ subunits of phosphorylase kinase, and partly activating enzyme activity. This binding partly stabilizes the protein in the active form. The phosphorylase kinase is completely activated when the β and α subunits are phosphorylated by protein kinase A and the delta subunit has bound to calcium ions. [2] [7] [20]

In muscle cells, phosphorylation of the α and β subunits by PKA is the result of a cAMP-mediated cell signaling cascade initiated by the binding of epinephrine to β-adrenergic receptors on the cell surface. Additionally, the release of calcium ions from the sarcoplasmic reticulum during muscle contraction inactivates the inhibitory δ subunit and activates PhK fully.

In liver cells, the process is somewhat more complex. Both glucagon and epinephrine can trigger the cAMP-PKA cascade, while epinephrine also binds to the α-adrenergic receptor to trigger a phosphoinositide cascade, resulting in the release of Ca2+ from the endoplasmic reticulum.

When the cell needs to stop glycogen breakdown, PhK is dephosphorylated by protein phosphatases 1 and 2, returning the α and β subunits to their initial inhibitory configuration. [21] [22]

Relation to disease

Defects in phosphorylase kinase genes are the cause of glycogen storage disease type IX (GSD type IX) and GSD type VI (formerly GSD type VIII), which can affect the liver and/or muscles. Among these gene defects, some of the most common are the X-linked liver glycogenosis (XLG) diseases, which can be subdivided into XLG I and XLG II. [23] [24] Clinically, these diseases manifest in slow childhood body development and abnormal enlargement of the liver. In XLG I, PhK activity is abnormally reduced in both blood cells and liver cells, while in XLG II enzyme activity is diminished only in liver cells. These diseases are both due to mutations in the PHKA2 gene, which codes for the α subunit of phosphorylase kinase. In the case of XLG I, mutations are often nonsense mutations which result in malformed, unstable α subunits, while mutations in XLG II tend to be missense changes which alter the subunits less severely. Based on bioinformatic and structural data, some have suggested that the α and β subunits may have catalytic activity similar to glycoamylases, and that missense mutations in these regions of the α subunit may contribute to the symptoms of XLG II. [25] [26] However, this proposed catalytic activity has yet to be proven directly.

See also

Related Research Articles

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Protein kinase A</span> Family of enzymes

In cell biology, protein kinase A (PKA) is a family of serine-threonine kinase whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase. PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase.

<span class="mw-page-title-main">AMP-activated protein kinase</span> Class of enzymes

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.

<span class="mw-page-title-main">Insulin receptor</span> Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

<span class="mw-page-title-main">Glycogen phosphorylase</span> Class of enzymes

Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

<span class="mw-page-title-main">Glycogen synthase</span> Enzyme class, includes all types of glycogen/starch synthases

Glycogen synthase is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.

<span class="mw-page-title-main">Glycogen debranching enzyme</span> Mammalian protein found in Homo sapiens

A debranching enzyme is a molecule that helps facilitate the breakdown of glycogen, which serves as a store of glucose in the body, through glucosyltransferase and glucosidase activity. Together with phosphorylases, debranching enzymes mobilize glucose reserves from glycogen deposits in the muscles and liver. This constitutes a major source of energy reserves in most organisms. Glycogen breakdown is highly regulated in the body, especially in the liver, by various hormones including insulin and glucagon, to maintain a homeostatic balance of blood-glucose levels. When glycogen breakdown is compromised by mutations in the glycogen debranching enzyme, metabolic diseases such as Glycogen storage disease type III can result.

Casein kinase 2 (CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumorigenesis as a potential protection mechanism for mutated cells. Proper CK2 function is necessary for survival of cells as no knockout models have been successfully generated.

<span class="mw-page-title-main">Myophosphorylase</span> Muscle enzyme involved in glycogen breakdown

Myophosphorylase or glycogen phosphorylase, muscle associated (PYGM) is the muscle isoform of the enzyme glycogen phosphorylase and is encoded by the PYGM gene. This enzyme helps break down glycogen into glucose-1-phosphate, so it can be used within the muscle cell. Mutations in this gene are associated with McArdle disease, a glycogen storage disease of muscle.

The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">PHKG1</span> Protein-coding gene in the species Homo sapiens

Phosphorylase b kinase gamma catalytic chain, skeletal muscle isoform is an enzyme that in humans is encoded by the PHKG1 gene.

<span class="mw-page-title-main">PHKG2</span> Protein-coding gene in the species Homo sapiens

Phosphorylase b kinase gamma catalytic chain, testis/liver isoform is an enzyme that in humans is encoded by the PHKG2 gene.

<span class="mw-page-title-main">Protein phosphatase 1</span>

Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen metabolism, muscle contraction, cell progression, neuronal activities, splicing of RNA, mitosis, cell division, apoptosis, protein synthesis, and regulation of membrane receptors and channels.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Ceramide-activated protein phosphatases (CAPPs) are a group of enzymes that are activated by the lipid second messenger ceramide. Known CAPPs include members of the protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) families. CAPPs are a subset of intracellular serine/threonine phosphatases. Each CAPP consists of a catalytic subunit which confers phosphatase activity and a regulatory subunit which confers substrate specificity. CAPP involvement has been implicated in glycogen metabolism, apoptotic pathways related to cancer and other cellular pathways related to Alzheimer’s disease.

Glycogen phosphorylase, liver form (PYGL), also known as human liver glycogen phosphorylase (HLGP), is an enzyme that in humans is encoded by the PYGL gene on chromosome 14. This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 14. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Feb 2011].

References

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  5. ↑ Fischer EH, Krebs EG (1955). "Conversion of phosphorylase b to phosphorylase a in muscle extracts". J Biol Chem. 216 (1): 121–132. doi: 10.1016/S0021-9258(19)52289-X . PMID   13252012.
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  8. ↑ Cohen P (1973). "The Subunit Structure of Rabbit-Skeletal-Muscle Phosphorylase Kinase, and the Molecular Basis of Its Activation Reactions". Eur J Biochem. 34 (1): 1–14. doi: 10.1111/j.1432-1033.1973.tb02721.x . PMID   4349654.
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  13. ↑ Johnson LN (2009). "The regulation of protein phosphorylation". Biochem Soc Trans. 37 (Pt 4): 627–641. doi:10.1042/BST0370627. PMID   19614568.
  14. 1 2 Vénien-Bryan C, et al. (2009). "The Structure of Phosphorylase Kinase Holoenzyme at 9.9 Å Resolution and Location of the Catalytic Subunit and the Substrate Glycogen Phosphorylase". Structure. 17 (1): 117–127. doi:10.1016/j.str.2008.10.013. PMC   2639635 . PMID   19141288.
  15. ↑ Wüllrich A, Hamacher C, Schneider A, Kilimann MW (1993). "The multiphosphorylation domain of the phosphorylase kinase alpha M and alpha L subunits is a hotspot of differential mRNA processing and of molecular evolution". J Biol Chem. 268 (31): 23208–23214. doi: 10.1016/S0021-9258(19)49449-0 . PMID   8226841.
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  18. ↑ Vénien-Bryan C, et al. (2002). "Three-dimensional structure of phosphorylase kinase at 22 A resolution and its complex with glycogen phosphorylase b". Structure. 10 (1): 33–41. doi: 10.1016/S0969-2126(01)00691-8 . PMID   11796108.
  19. ↑ Kilimann MW, et al. (1988). "The alpha and beta subunits of phosphorylase kinase are homologous: cDNA cloning and primary structure of the beta subunit". Proc Natl Acad Sci USA. 85 (24): 9381–9385. Bibcode:1988PNAS...85.9381K. doi: 10.1073/pnas.85.24.9381 . PMC   282756 . PMID   3200826.
  20. ↑ Heilmeyer LM (1991). "Molecular basis of signal integration in phosphorylase kinase". Biochim Biophys Acta. 1094 (2): 168–174. doi:10.1016/0167-4889(91)90005-I. PMID   1892899.
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  23. ↑ Hendrickx J, Willems PJ (1996). "Genetic deficiencies of the glycogen phosphorylase system". Hum Genet. 97 (5): 551–556. doi:10.1007/BF02281858. PMID   8655128. S2CID   23050104.
  24. ↑ Hendrickx J, et al. (1999). "Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II". Am J Hum Genet. 64 (6): 1541–1549. doi:10.1086/302399. PMC   1377897 . PMID   10330341.
  25. ↑ Pallen MJ (2003). "Glucoamylase-like domains in the α- and β-subunits of phosphorylase kinase". Protein Sci. 12 (8): 1804–1807. doi:10.1110/ps.0371103. PMC   2323967 . PMID   12876330.
  26. ↑ Carrière C, Jonic S, Mornon J, Callebaut I (2008). "3D mapping of glycogenosis-causing mutations in the large regulatory alpha subunit of phosphorylase kinase" (PDF). Biochim Biophys Acta. 1782 (11): 664–670. doi:10.1016/j.bbadis.2008.09.011. PMID   18950708.
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