A5071881971- Protein Kinase Regulation and GTPase Signaling
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Microtubule and mitosis dynamics
- Phosphodiesterase function and regulation
- Bioinformatics and Genomic Networks
- 14-3-3 protein interactions
- Mitochondrial Function and Pathology
- Melanoma and MAPK Pathways
- Gene Regulatory Network Analysis
- Genetic Neurodegenerative Diseases
- Signaling Pathways in Disease
- Cancer-related Molecular Pathways
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Cellular transport and secretion
- Protein Tyrosine Phosphatases
- PI3K/AKT/mTOR signaling in cancer
- Biochemical and Molecular Research
- Photosynthetic Processes and Mechanisms
- Trace Elements in Health
- Fungal and yeast genetics research
- Cellular Mechanics and Interactions
University of California, San Diego
2015-2024
University of Minnesota
2023
Goethe University Frankfurt
2023
Howard Hughes Medical Institute
2004-2014
University of San Diego
2010
Baylor College of Medicine
2009
San Diego Supercomputer Center
2004-2009
University College Dublin
2007
Scripps Research Institute
2004
Rutgers, The State University of New Jersey
2004
The surface comparison of different serine-threonine and tyrosine kinases reveals a set 30 residues whose spatial positions are highly conserved. between active inactive conformations identified the most sensitive to activation. Based on these results, we propose model protein kinase This explains how presence phosphate group in activation loop determines position catalytically important aspartate Asp-Phe-Gly motif. According model, feature is "spine" formation that dynamically assembled all...
Structures of set serine-threonine and tyrosine kinases were investigated by the recently developed bioinformatics tool Local Spatial Patterns (LSP) alignment. We report a conserved motifs comprised mostly hydrophobic residues. These residues are scattered throughout protein sequence thus not previously detected traditional methods. traverse kinase core play integrating regulatory roles. They anchored to F-helix, which acts as an organizing “hub” providing precise positioning key catalytic...
Significance Protein kinases represent a critically important family of regulatory enzymes. Their activity can be altered by mutations and binding events distant from the active site. To understand nature these long-distance effects, we used microsecond-timescale molecular dynamic simulation to subdivide prototypical kinase, protein kinase A, into contiguous communities that exhibit internally correlated motions. Surprisingly, most unconventional structural entities were centered around...
cAMP-binding domains from several different proteins were analyzed to determine the properties and interactions of this recognition motif. Systematic computational analyses, including structure-based sequence comparison, surface matching, affinity grid analysis, analyses ligand protein carried out. These show distinctive roles sugar phosphate adenine in module. We propose that regulatory function by providing an allosteric system which presence or absence cAMP produces a substantial...
Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that properly assembled nonlinear motif termed Regulatory (R) spine is essential for activity of EPKs. Here we define required intramolecular interactions and biochemical properties R-spine newly identified "Shell" surrounds using site-directed mutagenesis various in vitro...
In its physiological state, cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is a tetramer that contains regulatory (R) subunit dimer and two catalytic (C) subunits. We describe here the 2.3 angstrom structure of full-length tetrameric RIIβ(2):C(2) holoenzyme. This showing dimers provides mechanistic understanding allosteric activation by cAMP. The heterodimers are anchored together an interface created β4-β5 loop in RIIβ subunit, which docks onto carboxyl-terminal tail...
A new model of kinase regulation based on the assembly hydrophobic spines has been proposed. Changes in their positions can explain mechanism activation. Here, we examined mutations human cancer for clues about by focusing initially to Phe. We identified a selected number Phe small group kinases that included BRAF, ABL1, and epidermal growth factor receptor. Testing some these found one impaired ATP binding catalytic activity but promoted noncatalytic allosteric functions. Other functioned...
Because mutations in RAS and BRAF represent the most common found human tumors, identification of inhibitors has been a major goal. Surprisingly, new oncogenic specific inhibit cells transformed with mutated but paradoxically stimulate growth RAS. Here, we show that mechanism for activation is via drug-induced dimer formation between CRAF kinase suppressor Ras (KSR)1. To understand function KSR1, generated KSR1 mutant cannot bind ATP stabilizes closed, active conformation KSR1. Molecular...
Eukaryotic protein kinases (EPKs) constitute a class of allosteric switches that mediate myriad signaling events. It has been postulated EPKs' active and inactive states depend on the structural architecture their hydrophobic cores, organized around two highly conserved spines: C-spine R-spine. How spines orchestrate transition enzyme between catalytically uncommitted committed remains elusive. Using relaxation dispersion nuclear magnetic resonance spectroscopy, we found core catalytic...
Ligand-induced protein allostery plays a central role in modulating cellular signalling pathways. Here using the conserved cyclic nucleotide-binding domain of kinase A’s (PKA) regulatory subunit as prototype unit, we combine long-timescale, all-atom molecular dynamics simulations with Markov state models to elucidate conformational ensembles PKA’s A for cAMP-free (apo) and cAMP-bound states. We find that both systems exhibit shallow free-energy landscapes link functional states through...
Phosphorylation of an evolutionarily conserved motif by mTORC2 enables the maturation AGC kinases.
Significance Little is known about the regulation of Leucine-rich repeat kinase 2 (LRRK2) associated with familial Parkinson’s disease (PD). To test whether domain drives LRRK2 activation, we applied spine concept that describes core architecture every protein kinase. We discovered mutation Y2018, a regulatory residue, to Phe in DFGψ motif created hyperactive similar PD-associated G2019S. The hydroxyl moiety Y2018 thus serves as “brake,” stabilizing inactive conformation; simply removing it...