Alexey G Ryazanov

..This suggests that eEF-2 kinase and MHCK A are members of a new class of protein kinases with a novel catalytic domain structure...

..During aging, the concentration of damaged proteins increases because of decelerating protein turnover, the cause of which is unknown, however, it may be related to the decrease in ribosome concentration...

..The establishment of such a feedback loop should result in an exponential increase in the amount of protein damage-a protein damage catastrophe-that could be the basis of the general deterioration observed in senescent organisms...

..Several mammalian alpha-kinases have recently been cloned. Two of these alpha-kinases, named channel-kinases 1 and 2 (ChaK1 and ChaK2) represent a new type of signaling molecules that are protein kinases fused to ion channels...

..The N-terminal region plays a crucial role in interaction of annexin 1 with other proteins and membranes, and therefore, phosphorylation of annexin 1 at Ser5 by TRPM7 kinase may modulate function of annexin 1...

..Our results suggest that pH-dependent activation of eEF-2K may play a role in the global inhibition of protein synthesis during tissue acidosis, which accompanies such processes as hypoxia and ischemia...

..We also show that phosphorylation at Ser5 dramatically weakens the binding of the peptide to S100A11. Our data suggest that phosphorylation at Ser5 regulates the interaction of annexin A1 with membranes as well as S100A11 protein...

..Differences between alpha-kinases and CPKs, and their possible impact on substrate recognition are discussed...

..Ca(2+) at concentrations up to 1 mM did not affect kinase activity. Considering intracellular ion concentrations, our results suggest that, among divalent metal ions, only Mg(2+) can directly modulate TRPM7/ChaK1 kinase activity in vivo...

..elegans using RNAi. We showed that RNAi shortened the lifespan of both wild type and daf-2 mutant C. elegans, providing strong support for a role of autophagy in ageing regulation...

..The amino acid sequence of the carboxyl-terminal domain of eEF-2 kinase displays similarity to several proteins, all of which contain repeats of a 36-amino acid motif that we named "motif 36"...

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..Collectively, our results demonstrate that regulation of cell adhesion by TRPM7 is the combined effect of kinase-dependent and -independent pathways on actomyosin contractility...

..In conclusion, our data demonstrate that TRPM7 regulates myosin IIA filament stability and localization by phosphorylating a short stretch of amino acids within the alpha-helical tail of the myosin IIA heavy chain...

..1. We propose a model in which eEF2K-eEF2 and FMRP coordinately control the dynamic translation of Arc/Arg3.1 mRNA in dendrites that is critical for synapse-specific LTD...

..In conclusion, TRPM6 and TRPM7 share exogenous substrates among themselves but not with functionally distant alpha-kinases...

..Experiments will be performed to design and develop specific eEF-2 kinase inhibitors which can serve as pro- apoptotic agents. ..

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..The experiments described in this grant application are designed to provide a foundation for the development of novel therapeutic reagents that can mimic caloric restriction, circumventing some of the deleterious consequences of aging. ..

..This work will reveal the structural organization and function of a new class of protein kinases, which will provide new and important information about the mechanism of protein phosphorylation. ..

..2. To identify specific inhibitors of eEF2 kinase and to develop lead compounds that can be used to develop drugs that protect gastrointestinal tract from radiation damage. ..