Divalent metal ions control activity and inhibition of protein kinases

Metallomics ◽  
2017 ◽  
Vol 9 (11) ◽  
pp. 1576-1584 ◽  
Author(s):  
Matthias J. Knape ◽  
Mike Ballez ◽  
Nicole C. Burghardt ◽  
Bastian Zimmermann ◽  
Daniela Bertinetti ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Metal Ions ◽  
Protein Kinases ◽  
Substrate Binding ◽  
Divalent Metal ◽  
Catalytic Cycle ◽  
Divalent Metal Ions ◽  
Control Activity ◽  
Product Release

Metals like Zn2+ and Mn2+ can assist in the catalytic cycle of a protein kinase by facilitating substrate binding and phosphotransfer, however, in contrast to Mg2+ they also hamper product release.

scholarly journals Molecular Basis for Ser/Thr Specificity in PKA Signaling

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1548 ◽  
Author(s):  
Matthias J. Knape ◽  
Maximilian Wallbott ◽  
Nicole C. G. Burghardt ◽  
Daniela Bertinetti ◽  
Jan Hornung ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Substrate Specificity ◽  
Metal Ions ◽  
Protein Kinases ◽  
Molecular Basis ◽  
Kinase Inhibitor ◽  
Adenine Nucleotides ◽  
Catalytic Efficiency ◽  
Specific Protein ◽  
Divalent Metal Ions

cAMP-dependent protein kinase (PKA) is the major receptor of the second messenger cAMP and a prototype for Ser/Thr-specific protein kinases. Although PKA strongly prefers serine over threonine substrates, little is known about the molecular basis of this substrate specificity. We employ classical enzyme kinetics and a surface plasmon resonance (SPR)-based method to analyze each step of the kinase reaction. In the absence of divalent metal ions and nucleotides, PKA binds serine (PKS) and threonine (PKT) substrates, derived from the heat-stable protein kinase inhibitor (PKI), with similar affinities. However, in the presence of metal ions and adenine nucleotides, the Michaelis complex for PKT is unstable. PKA phosphorylates PKT with a higher turnover due to a faster dissociation of the product complex. Thus, threonine substrates are not necessarily poor substrates of PKA. Mutation of the DFG+1 phenylalanine to β-branched amino acids increases the catalytic efficiency of PKA for a threonine peptide substrate up to 200-fold. The PKA Cα mutant F187V forms a stable Michaelis complex with PKT and shows no preference for serine versus threonine substrates. Disease-associated mutations of the DFG+1 position in other protein kinases underline the importance of substrate specificity for keeping signaling pathways segregated and precisely regulated.

scholarly journals Divalent Metal Ions Mg2+and Ca2+Have Distinct Effects on Protein Kinase A Activity and Regulation

2015 ◽  
Vol 10 (10) ◽  
pp. 2303-2315 ◽  
Author(s):  
Matthias J. Knape ◽  
Lalima G. Ahuja ◽  
Daniela Bertinetti ◽  
Nicole C.G. Burghardt ◽  
Bastian Zimmermann ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Metal Ions ◽  
Protein Kinase A ◽  
Divalent Metal ◽  
Divalent Metal Ions ◽  
Kinase A

Structural and thermodynamic insights into a novel Mg2+–citrate-binding protein from the ABC transporter superfamily

2021 ◽  
Vol 77 (12) ◽  
Author(s):  
Suraj Kumar Mandal ◽  
Shankar Prasad Kanaujia
Keyword(s):  
Metal Ions ◽  
Abc Transporter ◽  
Metal Ion ◽  
Binding Protein ◽  
Substrate Binding ◽  
Divalent Metal ◽  
Uptake System ◽  
Divalent Metal Ions ◽  
Gram Negative ◽  
Divalent Metal Ion

More than one third of proteins require metal ions to accomplish their functions, making them obligatory for the growth and survival of microorganisms in varying environmental niches. In prokaryotes, besides their involvement in various cellular and physiological processes, metal ions stimulate the uptake of citrate molecules. Citrate is a source of carbon and energy and is reported to be transported by secondary transporters. In Gram-positive bacteria, citrate molecules are transported in complex with divalent metal ions, whereas in Gram-negative bacteria they are translocated by Na+/citrate symporters. In this study, the presence of a novel divalent-metal-ion-complexed citrate-uptake system that belongs to the primary active ABC transporter superfamily is reported. For uptake, the metal-ion-complexed citrate molecules are sequestered by substrate-binding proteins (SBPs) and transferred to transmembrane domains for their transport. This study reports crystal structures of an Mg2+–citrate-binding protein (MctA) from the Gram-negative thermophilic bacterium Thermus thermophilus HB8 in both apo and holo forms in the resolution range 1.63–2.50 Å. Despite binding various divalent metal ions, MctA possesses the coordination geometry to bind its physiological metal ion, Mg2+. The results also suggest an extended subclassification of cluster D SBPs, which are known to bind and transport divalent-metal-ion-complexed citrate molecules. Comparative assessment of the open and closed conformations of the wild-type and mutant MctA proteins suggests a gating mechanism of ligand entry following an `asymmetric domain movement' of the N-terminal domain for substrate binding.

Interaction of divalent metal ions with the NADP+-malic enzyme from maize leaves

1991 ◽  
Vol 81 (4) ◽  
pp. 462-466 ◽  
Author(s):  
Maria Fabiana Drincovich ◽  
Alberto A. Iglesias ◽  
Carlos S. Andreo
Keyword(s):  
Metal Ions ◽  
Malic Enzyme ◽  
Divalent Metal ◽  
Divalent Metal Ions ◽  
Maize Leaves

scholarly journals Regulation of divalent metal ions to the aggregation and membrane damage of human islet amyloid polypeptide oligomers

RSC Advances ◽  
2021 ◽  
Vol 11 (21) ◽  
pp. 12815-12825
Author(s):  
Yajie Wang ◽  
Feihong Meng ◽  
Tong Lu ◽  
Chunyun Wang ◽  
Fei Li
Keyword(s):  
Metal Ions ◽  
Metal Binding ◽  
Membrane Damage ◽  
Islet Amyloid Polypeptide ◽  
Divalent Metal ◽  
Human Islet ◽  
Divalent Metal Ions ◽  
Islet Amyloid ◽  
Induced Membrane ◽  
Human Islet Amyloid Polypeptide

Their is a counteraction between a decrease in the disruptive ability of metal-associated oligomer species and an increase in the quantity of oligomers promoted by the metal binding in the activity of hIAPP induced membrane damage.

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