title: Nucleotide release sequences in the protein kinase SRPK1 accelerate substrate phosphorylation.
abstract: Protein kinases are essential signaling enzymes that transfer phosphates from bound ATP to select amino acids in protein targets. For most kinases, the phosphoryl transfer step is highly efficient, while the rate-limiting step for substrate processing involves slow release of the product ADP. It is generally thought that structural factors intrinsic to the kinase domain and the nucleotide-binding pocket control this step and consequently the efficiency of protein phosphorylation for these cases. However, the kinase domains of protein kinases are commonly flanked by sequences that regulate catalytic function. To address whether such sequences could alter nucleotide exchange and, thus, regulate protein phosphorylation, the presence of activating residues external to the kinase domain was probed in the serine protein kinase SRPK1. Deletion analyses indicate that a small segment of a large spacer insert domain and a portion of an N-terminal extension function cooperatively to increase nucleotide exchange. The data point to a new mode of protein kinase regulation in which select sequences outside the kinase domain constitute a nucleotide release factor that likely interacts with the small lobe of the kinase domain and enhances protein substrate phosphorylation through increases in ADP dissociation rate.
authors: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093-0636, USA.
authors: Brandon E
authors: BE
authors: Aubol
authors: Ryan M
authors: RM
authors: Plocinik
authors: Maria L
authors: ML
authors: McGlone
authors: Joseph A
authors: JA
authors: Adams
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000378:metabolism; D017384:Sequence Deletion; D000068103:Serine-Arginine Splicing Factors
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D000244:Adenosine Diphosphate; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases