scholarly journals Design principles underpinning the regulatory diversity of protein kinases

2012 ◽  
Vol 367 (1602) ◽  
pp. 2529-2539 ◽  
Author(s):  
Krishnadev Oruganty ◽  
Natarajan Kannan
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Structural Features ◽  
Kinase Domain ◽  
Conformational Flexibility ◽  
Phosphoryl Transfer ◽  
Core Component ◽  
Protein Kinase Domain ◽  
The Core ◽  
Complex Modes

Protein phosphorylation in eukaryotes is carried out by a large and diverse family of protein kinases, which display remarkable diversity and complexity in their modes of regulation. The complex modes of regulation have evolved as a consequence of natural selection operating on protein kinase sequences for billions of years. Here we describe how quantitative comparisons of protein kinase sequences from diverse organisms, in particular prokaryotes, have contributed to our understanding of the structural organization and evolution of allosteric regulation in the protein kinase domain. An emerging view from these studies is that regulatory diversity and complexity in the protein kinase domain evolved in a ‘modular’ fashion through elaboration of an ancient core component, which existed before the emergence of eukaryotes. The core component provided the conformational flexibility required for ATP binding and phosphoryl transfer in prokaryotic kinases, but evolved into a highly regulatable domain in eukaryotes through the addition of exaggerated structural features that facilitated tight allosteric control. Family and group-specific features are built upon the core component in eukaryotes to provide additional layers of control. We propose that ‘modularity’ and ‘conformational flexibility’ are key evolvable traits of the protein kinase domain that contributed to its extensive regulatory diversity and complexity.

scholarly journals Analysis of Protein Kinase Domain and Tyrosine Kinase or Serine/Threonine Kinase signatures Involved In Lung Cancer

2014 ◽  
Author(s):  
Manas Ranjan Barik ◽  
Tripti Kaur Bagga ◽  
Anupam Bhattacharya ◽  
Bhagath Kumar Palaka ◽  
Kasi Viswanath Kotapati ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Phylogenetic Tree ◽  
Protein Kinases ◽  
Kinase Domain ◽  
Activation Process ◽  
Serine Threonine Kinase ◽  
Protein Kinase Domain ◽  
Threonine Kinase ◽  
Genetic Components

Lung cancer results when normal check and balance system of cell division is disrupted and ultimately the cells divide and proliferate in an uncontrollable manner forming a mass of cells in our body, known as tumor. Frequent mutations in Protein Kinase Domain alter the process of phosphorylation which results in abnormality in regulations of cell apoptosis and differentiation. Tyrosine Protein kinases and Serine/Threonine Protein Kinases are the two broad classes of protein kinases in accordance to their substrate specificity. The study of Tyrosine protein kinase and serine Kinase coding regions have the importance of sequence and structure determinants of cancer-causing mutations from mutation-dependent activation process. In the present study, we analyzed huge amounts of data extracted from various biological databases and NCBI. Out of the 534 proteins that may play a role in lung cancer, 71 proteins were selected that are likely to be actively involved in lung cancer. These proteins were evaluated by employing Multiple Sequence Alignment and a Phylogenetic tree was constructed using Neighbor-Joining Algorithm. From the constructed phylogenetic tree, protein kinase domain and motif study was performed. The results of this study revealed that the presence of Protein Kinase Domain and Tyrosine or Serine/Threonine Kinase signatures in some of the proteins are mutated, which play a dominant role in the pathogenesis of Lung Cancer and these may be addressed with the help of inhibitors to develop an efficient anticancer drugs. Furthermore, the present study contributes to the possibility that genetic components are more important in Lung Cancer as compared to environmental and smoking(carcinogens) factors.

scholarly journals Analysis of Protein Kinase Domain and Tyrosine Kinase or Serine/Threonine Kinase signatures Involved In Lung Cancer

2014 ◽  
Author(s):  
Manas Ranjan Barik ◽  
Tripti Kaur Bagga ◽  
Anupam Bhattacharya ◽  
Bhagath Kumar Palaka ◽  
Kasi Viswanath Kotapati ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Phylogenetic Tree ◽  
Protein Kinases ◽  
Kinase Domain ◽  
Activation Process ◽  
Serine Threonine Kinase ◽  
Protein Kinase Domain ◽  
Threonine Kinase ◽  
Genetic Components

Lung cancer results when normal check and balance system of cell division is disrupted and ultimately the cells divide and proliferate in an uncontrollable manner forming a mass of cells in our body, known as tumor. Frequent mutations in Protein Kinase Domain alter the process of phosphorylation which results in abnormality in regulations of cell apoptosis and differentiation. Tyrosine Protein kinases and Serine/Threonine Protein Kinases are the two broad classes of protein kinases in accordance to their substrate specificity. The study of Tyrosine protein kinase and serine Kinase coding regions have the importance of sequence and structure determinants of cancer-causing mutations from mutation-dependent activation process. In the present study, we analyzed huge amounts of data extracted from various biological databases and NCBI. Out of the 534 proteins that may play a role in lung cancer, 71 proteins were selected that are likely to be actively involved in lung cancer. These proteins were evaluated by employing Multiple Sequence Alignment and a Phylogenetic tree was constructed using Neighbor-Joining Algorithm. From the constructed phylogenetic tree, protein kinase domain and motif study was performed. The results of this study revealed that the presence of Protein Kinase Domain and Tyrosine or Serine/Threonine Kinase signatures in some of the proteins are mutated, which play a dominant role in the pathogenesis of Lung Cancer and these may be addressed with the help of inhibitors to develop an efficient anticancer drugs. Furthermore, the present study contributes to the possibility that genetic components are more important in Lung Cancer as compared to environmental and smoking(carcinogens) factors.

In silico profiling and structural insights of missense mutations in RET protein kinase domain by molecular dynamics and docking approach

2014 ◽  
Vol 10 (3) ◽  
pp. 421-436 ◽  
Author(s):  
C. George Priya Doss ◽  
B. Rajith ◽  
Chiranjib Chakraboty ◽  
V. Balaji ◽  
R. Magesh ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Protein Kinase ◽  
In Silico ◽  
Kinase Domain ◽  
Missense Mutations ◽  
Protein Kinase Domain ◽  
Docking Approach ◽  
Structural Insights

scholarly journals Insights into the phosphoryl transfer catalyzed by cAMP-dependent protein kinase

2014 ◽  
Vol 70 (a1) ◽  
pp. C449-C449
Author(s):  
Oksana Gerlits ◽  
Amit Das ◽  
Jianhui Tian ◽  
Malik Keshwani ◽  
Susan Taylor ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Active Site ◽  
Phosphate Group ◽  
Nucleoside Triphosphate ◽  
Phosphoryl Transfer ◽  
Hydrogen Atoms ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Protein kinases are involved in a number of cell signaling pathways. They catalyze phosphorylation of proteins and regulate the majority of cellular processes (such as growth, differentiation, lipid metabolism, regulation of sugar, nucleic acid synthesis, etc.). Chemically, protein kinases covalently transfer the gamma-phosphate group of a nucleoside triphosphate (e.g. ATP) to a hydroxyl group of a Ser, Thr or Tyr residue of substrate protein or peptide. The reaction involves moving hydrogen atoms between the enzyme, substrate and nucleoside. The unanswered question is whether the proton transfer from the Ser residue happens before the phosphoryl transfer using the general acid-base catalyst, Asp166, or after the reaction went through the transition state by directly protonating the phosphate group. To address this key question about the phosphoryl transfer, we determined a number of X-ray structures of ternary complexes of catalytic subunit of cAMP-dependent protein kinase (PKAc) with various substrates, nucleotides and cofactors. Importantly, we were able to trap and mimic the initial (Michaelis complex) and final (product complex) stages of the reaction. The results demonstrate that Mg2+, Ca2+, Sr2+, and Ba2+ metal ions bind to the active site and facilitate the reaction to produce ADP and a phosphorylated peptide. The study also revealed that metal-free PKAc can facilitate the phosphoryl transfer reaction; a result that was confirmed with single turnover enzyme kinetics measurements. Comparison of the product and the pseudo-Michaelis complex structures, in conjunction with molecular dynamics simulations, reveals conformational, coordination, and hydrogen bonding changes that help further our understanding of the mechanism, roles of metals, and active site residues involved in PKAc activity.

The Eukaryotic Protein Kinase Domain

2005 ◽  
pp. 181-209 ◽  
Author(s):  
Arvin C. Dar ◽  
Leanne E. Wybenga-Groot ◽  
Frank Sicheri
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Protein Kinase Domain ◽  
Eukaryotic Protein Kinase ◽  
Eukaryotic Protein

scholarly journals Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability

2017 ◽  
Vol 55 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Mark J Hamilton ◽  
Richard C Caswell ◽  
Natalie Canham ◽  
Trevor Cole ◽  
Helen V Firth ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Intellectual Disability ◽  
Protein Kinase ◽  
Developmental Delay ◽  
Congenital Heart ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Protein Kinase Domain

IntroductionRecent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.MethodsPatients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.ResultsOur cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.ConclusionsThese patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

scholarly journals Structural pathway for allosteric activation of the autophagic PI 3-kinase complex I

2019 ◽  
Vol 116 (43) ◽  
pp. 21508-21513 ◽  
Author(s):  
Lindsey N. Young ◽  
Felix Goerdeler ◽  
James H. Hurley
Keyword(s):  
Protein Kinase ◽  
Complex I ◽  
Structural Changes ◽  
Kinase Domain ◽  
Activation Loop ◽  
Class Iii ◽  
Lipid Kinase ◽  
Protein Kinase Domain ◽  
Autophagy Induction ◽  
Enzymatic Activation

Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the proautophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryoelectron microscopy was used to visualize a 2-step PI3KC3-C1 activation pathway driven by NRFB2 MIT domain binding. Binding of a single NRBF2 MIT domain bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes.

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