Phosphorylation plays a central role in all aspects of cellular biology. The complexity of the many similar enzymes within kinase families, often with different biological functions, has impacted our detailed understanding of signalling processes.
Breakthrough discoveries, however, have increased our understanding of the mechanisms that regulate kinase activity, and have shed light onto how activation of individual members of the same kinase family can trigger different signalling events.
To highlight these advances we are pleased to launch this Special Issue: Allosteric Regulation of Kinase Activity.
The articles in this Issue highlight how modern cellular, biochemical, biophysical and computational techniques are allowing deeper and more detailed studies of allosteric kinase regulation.
This Special Issue has been overseen by eLife Senior Editors Volker Dötsch, Goethe University, and Amy H Andreotti, Iowa State University, who take a look at the history of research in the area and the field today, and introduce the articles in the Special Issue in an editorial.
eLife introduced a new model of publishing in January 2023, and as a result this Special Issue includes research that has been through the traditional publishing process and Reviewed Preprints that have been through the new model.
Collection
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The articles in this special issue highlight how modern cellular, biochemical, biophysical and computational techniques are allowing deeper and more detailed studies of allosteric kinase regulation.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Structural and biochemical analysis of semisynthetic Akt forms and mutants has revealed the importance of a key interaction network involving Arg86, Glu17, and Tyr18 that controls Akt conformation and activity.
- Biochemistry and Chemical Biology
- Computational and Systems Biology
Key allosteric residues are predicted based on sequence coevolution analysis, which serves as guidelines for allosteric drug design and optimization.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The adaptor protein Grb2 is able to enhance the activity of the cytoplasmic tyrosine kinase Btk through a novel mechanism, revealing a new role for Grb2 in B-cell signaling.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
An entropy switch controls the Aurora B autoactivation process through two distinct kinetic steps of phosphorylation.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Regulation of phosphoinositide 3 kinase (PI3Kγ) is essential in immune function, and stimuli that modulate the dynamics of the PI3Kγ helical domain can activate or inhibit kinase activity.
- Biochemistry and Chemical Biology
- Immunology and Inflammation
A road to modulators of the kinase activity and the non-enzymatic functions of Src and IDO1 at once.
- Biochemistry and Chemical Biology
- Cell Biology
The functional role of novel regulatory mechanism within prototypic oncogenic kinase c-Src is described with particular emphasis on cancer cell migration, invasiveness, oncogenic transformation, and multilevel regulation of Src itself.
- Biochemistry and Chemical Biology
- Neuroscience
CaMKII is capable of spreading activity between holoenzymes without exchanging subunits.
- Computational and Systems Biology
- Evolutionary Biology
Isoform-specific variations in doublecortin-like kinases offer a new framework for understanding kinome-wide modulation of protein stability and catalytic activity.
- Biochemistry and Chemical Biology
A subtle mutation in the ATP-binding site of inositol hexakisphosphate kinases increases their conformational flexibility and thereby makes them susceptible to isozyme-selective, allosteric inhibition.
- Biochemistry and Chemical Biology
- Computational and Systems Biology
Mathematical modeling shows how RAF inhibitors can actually activate RAF kinases by stabilizing RAF proteins in the conformation capable of dimerization.
- Computational and Systems Biology
- Structural Biology and Molecular Biophysics
The cellular membrane competes with Abl for myristoyl binding to stabilize the preactivated state and enhance allosteric activation.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Protein kinase dysregulation, implicated in various diseases via cell signaling pathways, can be therapeutically and experimentally managed through allosteric modulation, facilitated by a dynamic network of interactions, with computational techniques enabling precise control in live systems.
- Cell Biology
- Developmental Biology
Phosphorylation of the pseudokinase Ulk4 by Stk36 promotes primary ciliary tip localization of both proteins to facilitate the phosphorylation and activation of Gli in response to Sonic hedgehog.
- Biochemistry and Chemical Biology
An in-depth binding profile analysis of BRAF domains related to RAF activation and autoinhibition unveils the distinctive roles of each domain in selecting preferred RAS isoforms and facilitating autoinhibition.
- Cell Biology
This article reviews the latest studies that have used super-resolution microscopy and cluster analysis methodologies to study the mechanism of protein kinase signalling hubs and their organisation at nanoscale.
- Computational and Systems Biology
- Immunology and Inflammation
KinCytE is a web-based platform that explores kinase-cytokine-driven signaling and its relevance to understanding and treating diseases linked to disruptions in these pathways.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The intrinsic disorder of the circadian clock protein Frequency organizes binding partners, facilitates liquid–liquid phase separation, modulates Frequency phosphorylation, and derives from sequence properties conserved with homologous clock components.
- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
A minimal subset of two to three residues in cyclic nucleotide binding (CNB) domains controls nucleoside vs. cyclic nucleotide specificity, repurposing PKA of certain pathogens for novel nucleoside signaling pathways or sensing.
- Biochemistry and Chemical Biology
New ATP-competitive inhibitors show properties of conformation selection when complexed with the MAP kinase, ERK2, altering movements around the activation loop.
- Cancer Biology
- Structural Biology and Molecular Biophysics
High-resolution NMR data and precise kinase activity assays on Abelson kinase bearing mutations in its αI-helix identify the αI-helix parts involved in disassembly of Abelson’s regulatory core and kinase activation.
- Structural Biology and Molecular Biophysics
Cryo-EM structures uncover glycosylation in the ectodomains of full-length HER4 homodimer and HER2/HER4 heterodimer complexes, revealing how the binding of various growth factors alters dynamics at the dimerization interface.
- Biochemistry and Chemical Biology
Single molecule reconstitution of PI3Kβ synergistic activation reveals mechanism for rapid PI(3,4,5)P3 production during immune cell signaling.
- Cancer Biology
Classification of MET mutations allows a better understanding of sensitivity and resistance to targeted therapies used in cancer.
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
A comprehensive allosteric model describes how inhibitors can activate rather than inhibit a target kinase by selectively driving formation of kinase dimers with one inhibited and one activated subunit.
- Structural Biology and Molecular Biophysics
The αC-β4 loop emerges as a hot spot for tuning allosteric cooperativity in the catalytic subunit of protein kinase A.
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