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  • br Conclusion br Competing interests br Funding

    2022-11-14


    Conclusion
    Competing interests
    Funding The Bolger Prostate Cancer Research Fund (no grant number), the National Institute of General Medical Sciences of the National Institutes of Health (1-R01-GM58553, G. B. Bolger, principal investigator), and the National Cancer Institute of the NIH to the University of Alabama at Birmingham Comprehensive Cancer Center under award number P30 CA013148 (for DNA sequencing).
    Authors' contributions
    Availability of data and materials
    Proteins determine the structural and functional phenotypes of Pam3CSK4 Biotin by regulating intrinsic metabolic and homeostatic processes and the responses of cells to environmental signals. Rates of protein synthesis are influenced by a variety of factors, including nutrient availability, energy metabolism, growth factors, aging, and disease states , , . When the organism and its cells are under energetic and oxidative stress, protein translation is limited to proteins critical for the survival and specific functions of the cells, including an array of adaptive stress response proteins . Neurons are particularly vulnerable to oxidative stress and associated membrane lipid peroxidation, which can destabilize cellular calcium homeostasis and trigger apoptosis , , , a form of programmed cell death mediated, in part, by p53 . Unmitigated lipid peroxidation contributes to the dysfunction and degeneration of neurons in both acute CNS injuries and neurodegenerative disorders including Alzheimer and Parkinson diseases . Protein synthesis is a complex process that determines both qualitative and quantitative features of the proteome , . If a particular protein is no longer required, inhibition of the initiation step of translation occurs; however, specific control of the elongation phase to rapidly alter production of particular proteins occurs under conditions such as heat shock and stimulation by hormones and growth factors , , , , , . In addition, some diseases are caused by abnormalities in elongation factors . Elongation factor-2 (eEF-2) is a fundamental regulatory protein of the translational elongation step that catalyzes the movement of the ribosome along the mRNA. eEF-2 is regulated by several mechanisms including phosphorylation , mono-ADP-ribosylation , , and protein–protein interactions , . A role for eEF-2 in cellular stress responses is highlighted by the fact that eEF-2 is sensitive to oxidative stress , and that it must be active, at least transiently, to drive the synthesis of proteins that help cells mitigate the adverse effects of oxidative stress or activate apoptosis if the extent of damage overwhelms the repair capacity.
    Synthetic biology of signal transduction The rational construction of artificial signaling systems is a key goal of synthetic biology. This encompasses all levels of complexity, ranging from proteins to pathways, networks, and, ultimately, organisms, and has application for molecular diagnostics, cell-based biosensors, therapeutics, and industrial biotechnology 1, 2. In addition, a capacity to engineer biological signaling systems with predictable behavior provides ultimate proof to scientific models describing biological processes [1]. Constructing artificial signaling systems has been realized predominantly with synthetic gene circuits, in which rational engineering strategies are supported by the modular organization and function of transcription factors and their DNA response elements 3, 4. Similarly, aptamers and ribozymes have been recombined to create functional nucleic acids that can sense and amplify distinct molecular cues [5] or exert post-transcriptional control on gene expression [6]. However, the limited chemical diversity of nucleic acids compared with amino acids ultimately limits their functionality. Furthermore, transcription-based signaling circuits are inherently slow, with typical response times on the scale of hours [7]. By contrast, protein-based signaling circuits operate orders of magnitude faster and feature diverse enzymatic outputs [7]. However, engineering such systems has proven challenging, especially at the molecular level, where signaling is controlled by distinct protein switches. These can either be based on allosterically regulated proteins that couple input to output solely through conformational changes or be composed of modular receptors, transducers, and actuators that process molecular cues in a concerted fashion through the induced colocalization of distinct signaling components. The individual designs can range from highly integrated based on structurally intertwined receptors and actuators, where conformational changes are transmitted through networks of residues that are adjacent in tertiary, but not necessarily in primary structure (Figure 1A), to modular, where conformational changes are limited to the linker regions that separate functionally and structurally distinct receptor and actuator domains (Figure 1B), to highly modular, where signaling cues are transmitted through the induced colocalization of molecularly distinct signaling components (Figure 1C).