Elements of Signal Transduction

Autophosphorylation and phosphorylation of substrate proteins are essential elements of signal transduction via receptor tyrosine kinases. Autophosphorylation fre-... 

A particular feature of the two-component system is the use of phosphohistidine and phosphoaspartate groupings (see Fig. 7.1) as elements of signal transduction. The... 

Via, L.E. Curcic, R. Mudd, M.H. Dhandayuthapani, S. Ulmer, R.J. Dere-tic, V, Elements of signal transduction in Mycobacterium tuberculosis in vitro phosphorylation and in vivo expression of the response regulator MtrA. J. BacterioL, 178, 3314-3321 (1996)... 

This review will focus on enzymes converting sterols, but will not deal with proteins representing elements of signal transduction cascades, i.e. kinases or receptors. 

A particular feature of the two-component system is the use of phosphohistidine and phosphoaspartate groupings (see Fig. 7.1) as elements of signal transduction. The phosphonamide grouping in phosphohistidine is unstable in aqueous medium and has only a short half-life. The duration of the signal transduction is thus limited to a large extent by the chemical instability of phosphohistidine. 

ELEMENTS OF SIGNAL TRANSDUCTION 405 active/inactive = on/off = kdis/kcai... 

Calculation of Conformational Free Energies for a Model of a Bilobal Enzyme Protein kinases catalyze the transfer of phosphate from adenosine triphosphate (ATP) to protein substrates and are regulatory elements of most known pathways of signal transduction. 

Some cytokine receptors can directly initiate signal transduction upon binding of ligand. In other cases additional elements are involved. For many receptors, the exact intracellular events triggered upon ligand binding remain to be elucidated. However, the molecular details of signal transduction pathways for others (e.g. the interferons) are now understood... 

All interferon-stimulated genes are characterized by the presence of an associated interferon-stimulated response element (ISRE). Signal transduction culminates in the binding of specific regulatory factors to the ISRE, which stimulates RNA polymerase Il-mediated transcription of the interferon-sensitive genes. The induced gene products then mediate the antiviral, immunomodulatory and other effects characteristically induced by interferons. 

Fig. 3.6. Principles of signal transduction by transmembrane receptors and nuclear receptors, a) transmembrane receptors receive the signal on the cell surface and convert it into an intracellular signal that can be passed on until it reaches the nucleus, b) In signal transduction via nuclear receptors the hormone enters the cell and binds the receptor either in the cytosol (R) or nucleus (R ). Nuclear receptors act as nuclear transcription factors that bind specific DNA elements (HRE hormone responsive element) found in the promotor region of regulated genes to control their transcription rate.

Fig. 4.4. The principle of signal transduction by nuclear receptors. Nuclear receptors are ligand-controlled transcription factors that bind cognate DNA sequences, or hormone responsive elements (HRE). The hormone acts as a regulating ligand. Most nuclear receptors bind their cognate HREs, which tend to be symmetrically organized, as homo- or heterodimers. The DNA-bound, activated receptor stimulates transcription initiation via direct or indirect protein-protein interactions with the transcription initiation complex. The arrows demonstrate the different possible configurations of the HRE (see also 4.6). H hormone Hsp heat shock protein.

Identification of multiple input signals and several effector proteins underlines the high complexity of signal transduction via the Ras protein. The Ras pathway cannot be seen as a linear ordering of signal elements, by which information is conducted verti-... 

Fig. 11.8. Scheme of signal transduction via interferon a. The receptor for interferon a (IFNa) binds and activates the Jak kinases Jakl and Tykl. These phosphorylate the Stat factors Statl and Stat2, leading to formation of Statl-Stat2 heterodimers. The heterodimers are transported into the nucleus and bind to a corresponding DNA element known as ISRE (interferon stimulated response element). Another protein, p48, is also involved in transcription activation of the interferon regulated gene. 

At the DNA level, variability of the DNA elements specific for Stat proteins and accessibility of the promoter sites are further determining factors for specificity of signal transduction. 

The two-component pathway is characterized by two functional elements. A histidine-specific protein kinase functions as a sensor that registers an external signal and passes this on to a downstream response regulator. The latter is activated by phosphorylation during the process of signal transduction, triggering other reactions in the cell (Fig. 12.3). 

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