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Eukaryotic protein kinases are enzymes that transfer a phosphoryl group (-PO<sub>3</sub><sup>2-</sup>) from adenosine triphosphate (or more rarely from adenosine diphosphate) to the hydroxyl group of serine, threonine, or tyrosine residue of a protein substrate. Phosphorylation of the substrate can affect its activity and/or conformation and, in turn, the physiogy of the cell. Protein kinases act as switches that turn on or off metabolic and signaling pathways, and they play central roles in development and responses to the environment. Also, unregulated versions of kinases that arise from tumor-promoting viruses promote cancer in humans. The number of protein kinase genes (and the percentage of the genome) in bakers yeast<ref>PMID: 9020587</ref>, humans<ref> PMID:12471243</ref> and rice <ref>PMID:17172291</ref> are 113 (2%),518 (2%), and 1429 (5%), respectively. The catalytic domains of these enzymes occur alone or with other functional domains in a single polypetide chain. Protein kinases may be monomeric or multimeric or found in complexes with regulatory proteins. | Eukaryotic protein kinases are enzymes that transfer a phosphoryl group (-PO<sub>3</sub><sup>2-</sup>) from adenosine triphosphate (or more rarely from adenosine diphosphate) to the hydroxyl group of serine, threonine, or tyrosine residue of a protein substrate. Phosphorylation of the substrate can affect its activity and/or conformation and, in turn, the physiogy of the cell. Protein kinases act as switches that turn on or off metabolic and signaling pathways, and they play central roles in development and responses to the environment. Also, unregulated versions of kinases that arise from tumor-promoting viruses promote cancer in humans. The number of protein kinase genes (and the percentage of the genome) in bakers yeast<ref>PMID: 9020587</ref>, humans<ref> PMID:12471243</ref> and rice <ref>PMID:17172291</ref> are 113 (2%),518 (2%), and 1429 (5%), respectively. The catalytic domains of these enzymes occur alone or with other functional domains in a single polypetide chain. Protein kinases may be monomeric or multimeric or found in complexes with regulatory proteins. | ||
This article | This first section of this article relates the protein kinase subdomains defined by analysis of the primary structure of protein kinases via alignment of amino acid sequences <ref name='Hanksa'>PMID:3291115</ref><ref name='Hanksb'>PMID: 7768349</ref> to the three-dimensional structure of protein kinase A (also called PKA or [[CAMP-dependent protein kinase]]) by Knighton et al.<ref> PMID: 1862342</ref> The results described in these papers apply to the basic structure of the great range of eukaryotic protein kinases known today. | ||
The crystal structure [[1atp]] contains the mouse PKA catalytic subunit (blue cartoon), inhibitor protein PKI (yellow cartoon), ATP (CPK wireframe), and two manganese ions (green spheres). The model at the left illustrates that catalytic domains of eukaryotic protein kinases have a small lobe and a large lobe (seen at the top and bottom of the model, respectively), and the catalytic cleft is located between them. The small lobe binds ATP and the large lobe binds the protein substrate modeled here by the inhibitor peptide, which has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions. | The crystal structure [[1atp]] contains the mouse PKA catalytic subunit (blue cartoon), inhibitor protein PKI (yellow cartoon), ATP (CPK wireframe), and two manganese ions (green spheres). The model at the left illustrates that catalytic domains of eukaryotic protein kinases have a small lobe and a large lobe (seen at the top and bottom of the model, respectively), and the catalytic cleft is located between them. The small lobe binds ATP and the large lobe binds the protein substrate modeled here by the inhibitor peptide, which has an alanine substituted for the serine in the phosphorylation motif RRxS. All of the molecular scenes include ATP, and some include the inhibitor peptide to illustrate kinase/substrate interactions. | ||
=Twelve Conserved Subdomains= | ==Twelve Conserved Subdomains== | ||
Following is a tour of the twelve conserved subdomains (numbered starting at the amino terminal end of the catalytic domain) defined by Hanks and Hunter and using 1atp as a model. | Following is a tour of the twelve conserved subdomains (numbered starting at the amino terminal end of the catalytic domain) defined by Hanks and Hunter and using 1atp as a model. | ||
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<scene name='55/555705/Subdomainx/1'>Subdomain X</scene> and <scene name='55/555705/Subdomainxi/1'>Subdomain XI</scene> contain three alpha helices (G, H, and I in mamallian PKA) that form the kinase core and which are involved in binding substrate proteins. | <scene name='55/555705/Subdomainx/1'>Subdomain X</scene> and <scene name='55/555705/Subdomainxi/1'>Subdomain XI</scene> contain three alpha helices (G, H, and I in mamallian PKA) that form the kinase core and which are involved in binding substrate proteins. | ||
=Beyond the Conserved Subdomains= | ==Beyond the Conserved Subdomains== | ||
===Functional units and assemblies=== | |||
Functional structures that involve residues from more than one subdomain have been recognized by biochemical and molecular genetic studies coupled with three-dimensional structures of protein kinases. | Functional structures that involve residues from more than one subdomain have been recognized by biochemical and molecular genetic studies coupled with three-dimensional structures of protein kinases. | ||
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The <scene name='55/555705/Gatekeeper-subdomainv/2'>"gatekeeper"</scene> residue<ref name="TaylorTIBS"/> (chartreuse spacefill) is a part of subdomain V (blue) and it is located deep in the ATP-binding pocket (Subdomain I with its ATP binding loop are shown in yellow). The size of the gatekeeper residue determines the size of the binding pocket, and it is thus a gatekeeper for which nucleotides, ATP analogs, and inhibitors can bind<ref> PMID: 15908922 </ref>. In PKA and about 75% of all kinases it is a large residue, such as leucine, phenylalanine or methionine as seen here. In the remaining kinases, especially tyrosine kinases, the residue is larger, such as threonine or valine. The gatekeeper's location is <scene name='55/555705/Gatekeeper-spines/2'>between the two hydrophobic spines </scene><ref name="TaylorTIBS"/> (gatekeeper is chartreuse, catalytic spine is blue, regulatory spine is orchid). Mutation of this residue in some kinases leads to activation of the kinase via enhanced autophosphorylation of the activation loop, and the unregulated kinase activity promotes cancer <ref name='one'>PMID: 17114285</ref><ref name='two'>PMID: 18794843</ref>. The gatekeeper's interaction with the two spines affects the orientation of the catalytic, magnesium binding, and activation loops. | The <scene name='55/555705/Gatekeeper-subdomainv/2'>"gatekeeper"</scene> residue<ref name="TaylorTIBS"/> (chartreuse spacefill) is a part of subdomain V (blue) and it is located deep in the ATP-binding pocket (Subdomain I with its ATP binding loop are shown in yellow). The size of the gatekeeper residue determines the size of the binding pocket, and it is thus a gatekeeper for which nucleotides, ATP analogs, and inhibitors can bind<ref> PMID: 15908922 </ref>. In PKA and about 75% of all kinases it is a large residue, such as leucine, phenylalanine or methionine as seen here. In the remaining kinases, especially tyrosine kinases, the residue is larger, such as threonine or valine. The gatekeeper's location is <scene name='55/555705/Gatekeeper-spines/2'>between the two hydrophobic spines </scene><ref name="TaylorTIBS"/> (gatekeeper is chartreuse, catalytic spine is blue, regulatory spine is orchid). Mutation of this residue in some kinases leads to activation of the kinase via enhanced autophosphorylation of the activation loop, and the unregulated kinase activity promotes cancer <ref name='one'>PMID: 17114285</ref><ref name='two'>PMID: 18794843</ref>. The gatekeeper's interaction with the two spines affects the orientation of the catalytic, magnesium binding, and activation loops. | ||
===Active and inactive structures=== | |||
=References= | =References= | ||
<references/> | <references/> | ||