Posttranslational modifications regulators

Schdnichen, A, Webb, B. A., Jacobson, M. P., and Barber, D. L. [2013]. Considering protonation as a posttranslational modification regulating protein structure and function. Annual Review of Biophysics 42,1, pp. 289-314. 

The transcriptional activity of NRs is also modulated by various posttranslational modifications of the receptors themselves or of their coregulatory proteins. Phosphorylation, as well as several other types of modification, such as acetylation, SUMOylation, ubiquitinylation, and methylation, has been reported to modulate the functions of NRs, potentially constituting an important cellular integration mechanism. In addition to the modifications of the receptors themselves, such modifications have been reported for their coactivators and corepressors. Therefore, these different modes of regulation reveal an unexpected complexity of the dynamics of NR-mediated transcription. 

In the x-ray structure of rhodopsin, an amphipathic helix runs parallel to the membrane from the intracellular end of TM-VII beneath the seven-helical bundle to the other side of TM-I and TM-II. At this point, one or more Cys residues are often found and are known to be subject to a dynamic posttranslational modification with palmitic acid residues. Like the phosphorylation event, the palmitoylation process appears to be dynamically regulated by receptor occupancy and is also involved in the desensitization phenomenon. The two posttranslational modifications can influence each other. For example, the conformational constraint induced by palmitoylation may alter the accessibility of certain phosphorylation sites. Like the phosphorylation process, the functional consequences of palmitoylation also appear to vary from receptor to receptor. 

Figure 1 Covalent modifications of DNA and histones play a fundamental role in the regulation of differentiation and development. The writers, readers, and erasers of this dynamic code are potentially amenable to modulation with small molecules. Lysine methylation is a critical posttranslational modification influencing chromatin function (PMT = protein lysine methyltransferase, royal family proteins bind KMe, KDM = lysine demethylase).

Ran (the Ras-related nuclear protein) is the major regulator of nucleo-cytoplas-mic transport [134] across the nuclear pore complex (NPC). Like other small Ras-like GTP-binding proteins, it switches between a GTP- and a GDP-bound form by GTP-hydrolysis and nucleotide exchange [135]. In contrast to its relatives, Ran does not undergo posttranslational modification. 

Crawford, R., et. al., 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the regulation and posttranslational modification of p27kipl in lipopolysaccharide-activated B cells, Toxicol. Sci., 75, 333, 2003. 

Cell cycle progression, apoptosis, DNA damage and DNA repair are cellular functions that are regulated by several mechanisms. One such important regulatory mechanism is posttranslational modification of histone and non-histone proteins. Myriad of reports have been shown that acetylation of non-histone proteins apart from histones, contributes in major to these processes. 

Figure 3. Role of nonhistone protein acetylation in maintaining cellular homeostasis- mis-regulation and disease connection (a) Acetylation of nonhistone proteins are associated with active or repressed chromatin architecture as guided by suitable cellular signals for maintenance of gene expression. Misreg-ulation of HAT function leads to diseased state, where chromatin architecture is altered than under normal condition. In a parallel way the posttranslational modification status of these proteins may act as versatile tool to diagnose the various stages of disease manifestation e.g. probable involvement of acetylated NPMl modulating its stress response function can lead us to use it as a marker for various disease states, (b) Acetylation of nonhistone proteins in connection to diseases like Cancer, AIDS, Diabetes and others. (See Colour Plate 14.)...

Methylation plays an important role in transcriptional regulation and a lesser role in signal transduction. " Histones are heavily methylated proteins. Single, double, or triple methylated lysines play an important role on histones. Lysine methylation is a more subtle transcriptional control than acetylation. Lysine methylation has come to light in another protein known as p53. p53 is a protein expressed in low levels in the cell and stabilized by posttranslational modifications including phosphorylation, acetylation, and now N-methylation. There are several C-terminal lysines on p53 that increase its stability. The addition of the methylation modifications adds complexity to p5 3 and fine-tunes its activity and ultimately suppresses tumor formation. ... 

Posttranslational modifications are a sundry set of transformations that help to diversify the limited genome of organisms. The modifications discussed in this chapter have been shown to modify a wide variety of proteins whose functions vary from cell division to metabolism and regulation. While a large selection of posttranslational modifications has been discussed, the presentation is not all-inclusive of all modifications. Emphasis has been placed on the discoveries made since 2005 and on the more common modifications. The importance of posttranslational modifications on protein structure and function and cellular function has been emphasized. 

Protein substrates are degraded in the cell at specific times in response to physiological stimuli. In addition, degradation of substrates is probably spatially restricted within a cell. Based on accumulated evidence, it appears that the vulnerability or resistance to ubiquitin—proteasome-mediated degradation is regulated usually by a posttranslational modification. The protein substrates are modified in two main ways (1) by phosphorylation or (2) by allosteric modifications. 

Ubiquitin ligases largely control the substrate specificity of ubiquitin-conjugation reaction. The temporal specificity of ubiquitin conjugation to substrates by these enzymes is provided by regulation of the ligase activity. Activity of ubiquitin ligases can be modulated by posttranslational modification such as phosphorylation and by allosteric modification of the enzyme, or by attachment to UbL proteins. 

The resolving power of mass spectroscopy is further exemplified in posttranslational modification studies of acyl carrier protein from Mycobacterium tuberculosis. Researchers were able to determine both the nature of the modification and also the mechanism by which the protein was regulated (Fung et al., 2001, Reference 7). 

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