Phosphoprotein-protein interactions revealed by the crystal structure of kinase-associated phosphatase in complex with phosphoCDK2.
The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity. Here we describe the crystal structure of KAP in association with pThr-160-CDK2, representing an example of a protein phosphatase in complex with its intact protein substrate. The major protein interface between the two molecules is formed by the C-terminal lobe of CDK2 and the C-terminal helix of KAP, regions remote from the kinase-activation segment and the KAP catalytic site. The kinase-activation segment interacts with the catalytic site of KAP almost entirely via the phosphate group of pThr-160. This interaction requires that the activation segment is unfolded and drawn away from the kinase molecule, inducing a conformation of CDK2 similar to the activated state observed in the CDK2/cyclin A complex.
Song
H
H
Department of Biochemistry, University of Oxford, United Kingdom.
Hanlon
N
N
Brown
N R
NR
Noble
M E
ME
Johnson
L N
LN
Barford
D
D
D000595:Amino Acid Sequence; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D002384:Catalysis; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018844:Cyclin-Dependent Kinases / Q000737:chemistry* / Q000378:metabolism*; D054637:Dual-Specificity Phosphatases; D006801:Humans; D008958:Models, Molecular; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry
D019925:Cyclin A; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D010750:Phosphoproteins; D010769:Phosphothreonine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; C084429:CDKN3 protein, human; D054637:Dual-Specificity Phosphatases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases