Dynamics of signaling by PKA

Taylor, Susan S.; Kim, Choel; Vigil, Dominico; Haste, Nina M.; Yang, Jie; Wu, Jian; Anand, Ganesh S.

doi:10.1016/j.bbapap.2005.08.024

Cited by 221 publications

(202 citation statements)

References 53 publications

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…That the intact RSK1 consensus phosphorylation sequence on the pseudosubstrate region of PKARI␣ is required for its interaction with the NTK of RSK1 suggests that the catalytic cleft of the NTK is involved in the interactions. The catalytic cleft residues in PKAc also contact the pseudosubstrate site on PKARI␣ and the cognate inhibitory region on PKARII with a resultant inhibition of PKAc activity (7,8,28). In the case of RSK1, however, the inactive, but not the active form of RSK1 associates with PKARI␣ (20,21), and substitution of Ser-221 with Asp abrogates this interaction, suggesting that the Ser-221 phosphorylation or a negative charge at this site alters the orientation of the residues in the NTK catalytic cleft, which interacts with the pseudosubstrate site on PKARI␣.…”

Section: Discussionmentioning

confidence: 99%

“…2) and PKAc (7,8,28) bind the pseudosubstrate region of PKARI␣, we reasoned that PKAc and RSK1 might compete for binding to PKARI␣. In support of this notion, we had previously observed that the association of RSK1 with PKARI␣ decreased the interactions between PKAc and PKARI␣ (20).…”

Section: Pkac and Rsk1 Compete For Binding To Pkari␣ And This Competmentioning

confidence: 99%

“…The heterotetrameric form of the PKA holoenzyme is inactive, and the binding of two cAMP molecules to each of the regulatory subunits causes dissociation of PKAc, resulting in its activation (3,4). Both PKARI and PKARII, via binding of their pseudosubstrate and inhibitory regions, respectively, to the catalytic cleft of PKAc, inhibit its activity (5)(6)(7)(8). However, other regions of PKARI␣ also interact with the large lobe of PKAc (7).…”

mentioning

confidence: 99%

See 2 more Smart Citations

p90 Ribosomal S6 Kinase 1 (RSK1) and the Catalytic Subunit of Protein Kinase A (PKA) Compete for Binding the Pseudosubstrate Region of PKAR1α

Gao

Chaturvedi

Patel

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Pkac and Rsk1 Compete For Binding To Pkari␣ And This Competmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

p90 Ribosomal S6 Kinase 1 (RSK1) and the Catalytic Subunit of Protein Kinase A (PKA) Compete for Binding the Pseudosubstrate Region of PKAR1α

Gao

Chaturvedi

Patel

2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…3A). Unsurprisingly, this ATP-dependent substrate interaction appears to be a wider kinase mechanism as it also exists for two strong-binding pseudo-peptides for PKA (19) (Fig. 3B).…”

Section: Resultsmentioning

confidence: 99%

“…PKA sensors contained either the pseudosubstrate peptide from the type I␣ regulatory subunit of protein kinase A (RI␣ Pep ; KGRRRRGAISAEV) or a peptide derived from protein kinase inhibitor protein (PKI Pep ; TTYAD-FIASGRTGRRNAIHD) (Fig. 3B) (19). Human PKC␣ cDNA was purchased from Open Biosystems as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

Substrate Affinity Differentially Influences Protein Kinase C Regulation and Inhibitor Potency

Sommese¹,

Sivaramakrishnan

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The overlapping network of kinase-substrate interactions provides exquisite specificity in cell signaling pathways, but also presents challenges to our ability to understand the mechanistic basis of biological processes. Efforts to dissect kinase-substrate interactions have been particularly limited by their inherently transient nature. Here, we use a library of FRET sensors to monitor these transient complexes, specifically examining weak interactions between the catalytic domain of protein kinase C␣ and 14 substrate peptides. Combining results from this assay platform with those from standard kinase activity assays yields four novel insights into the kinase-substrate interaction. First, preferential binding of non-phosphorylated versus phosphorylated substrates leads to enhanced kinase-specific activity. Second, kinase-specific activity is inversely correlated with substrate binding affinity. Third, high affinity substrates can suppress phosphorylation of their low affinity counterparts. Finally, the substrate-competitive inhibitor bisindolylmaleimide I displaces low affinity substrates more potently leading to substrate selective inhibition of kinase activity. Overall, our approach complements existing structural and biophysical approaches to provide generalizable insights into the regulation of kinase activity.The canonical role of a protein kinase is to recognize, bind, and phosphorylate specific serine, threonine, or tyrosine residues on a substrate protein (1, 2). Given that kinases are one of the largest gene families in eukaryotes and are involved in nearly every cellular function (3), significant work has focused on understanding the mechanisms that dictate substrate-kinase pairings (4). Although the catalytic domains of eukaryotic kinases are structurally conserved (5, 6), the local environment around the substrate binding pocket of the kinase catalytic domain varies between kinases (7). This has led to the view that phosphorylation site recognition occurs through conserved residues flanking the phospho-residue on the substrate. Linear sequence motifs have now been identified for most kinases through a combination of structural analysis and peptide libraries (4, 8). Additionally, these phospho-sites are frequently found in unstructured regions of the substrate protein that may allow for more flexible accommodation in the kinase active site (9, 10). After recognizing the substrate, the catalytic domain then transfers a phosphate group from ATP to the phosphoresidue on the substrate. Phospho-transfer is followed by release of ADP and the phosphorylated substrate to prime the kinase for another catalytic cycle (11).Crystallographic and NMR approaches have provided detailed structural information on the catalytic domains of individual kinases in complex with a variety of nucleotide analogs and inhibitors (6, 12, 13). However, the lack of defined secondary structure surrounding the phospho-motif and the inherent transient nature of the interaction has limited efforts to dissect the different states of the ...

show abstract

Approaches to Kinase Homology Modeling: Successes and Considerations for the Structural Kinome

Feher

Lawson

2009

Kinase Inhibitor Drugs

View full text Add to dashboard Cite

Dynamics of signaling by PKA

Cited by 221 publications

References 53 publications

p90 Ribosomal S6 Kinase 1 (RSK1) and the Catalytic Subunit of Protein Kinase A (PKA) Compete for Binding the Pseudosubstrate Region of PKAR1α

p90 Ribosomal S6 Kinase 1 (RSK1) and the Catalytic Subunit of Protein Kinase A (PKA) Compete for Binding the Pseudosubstrate Region of PKAR1α

Substrate Affinity Differentially Influences Protein Kinase C Regulation and Inhibitor Potency

Approaches to Kinase Homology Modeling: Successes and Considerations for the Structural Kinome

Contact Info

Product

Resources

About