Signal transduction principles

In this chapter we describe some examples of structures of membrane-bound proteins known to high resolution, and outline how the elucidation of these structures has contributed to understanding the specific function of these proteins, as well as some general principles for the construction of membrane-bound proteins. In Chapter 13 we describe some examples of the domain organization of receptor families and their associated proteins involved in signal transduction through the membrane. 

The best approach for dealing with signal transduction pathways (as always, in my opinion) is to learn the various kinds of general pathways that exist and then try to fit new pathways onto these types. There are a few general principles of signal transduction pathways that can be used to organize your approach. 

It is important to appreciate that this principle of coupling-in-series underlies all biochemical pathways or processes, e.g. glycolysis, generation of ATP in the mitochondrion, protein synthesis from amino acids or a signal transduction pathway. Indeed, despite the fundamental importance of signalling pathways in biochemistry, a thermodynamic analysis of such a pathway has never been done, but the principles outlined above must apply even to signalling pathways. 

In the following we will deal with the basic components and principles of intracellular signal transduction and signal processing. The specific reactions and levels of signal transduction will be dealt with in detail in later chapters. 

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. 3.8. Variability of receptor systems and signal pathways, a) For one receptor of a given binding specificity (binding to hormone H) there can be different snbtypes in the same ceU (Rl, R2) or in other cell types (Rl )- b) The hormone H can induce different reactions (X, X ) upon binding the different receptor types (Rl, R2). The receptor types Rl and R2 can be found simultaneous in one cell, c) the binding of two different hormones (H, H ) to different receptors (Rl , R3) can induce the same intracellular reaction. The characteristics a) and b) contribute to a high degree to the diversity and variability of hormonal signal transduction. Point c) illustrates the principle that important cellular metabolites or reactions can be controlled by different signal transduction pathways.

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.

Fig. 4.10. Principle of signal transduction by steroid hormone receptors. The steroid hormone receptors in the cytosol are found in the form of an inactive complex with the heat shock proteins Hsp90 and Hsp56 and with protein p23. The binding of the hormone activates the receptor so that it can be transported into the nucleus where it binds to its cognate HRE. It remains unclear in which form the receptor is transported into the nucleus, and to which extent the associated proteins are involved in the transport. One mechanism of activation of transcription initiation involves activation of a histone acetylase and remodehng of chromatin. Furthermore, the receptors interact directly or indirectly with components of the RNA polymerase II holoenzyme (e.g. SUGl).

Fig. 4.11. Principle of signal transduction by RXR heterodimers. The activated hormone can be made available to the RXR heterodimer in three different ways, a) The hormone (e.g. T3 hormone) is synthesized in endocrinal tissue and reaches the DNA-bound RXR-T3R heterodimer in the nucleus via passive transport, b) The active hormone is formed in the cytosol from an inactive apo-hormone (as for, e.g. 9-ds-retinoic add), c) The hormone is synthesized intracellularly. In aU three cases, the binding of the hormone-RXR-heterodimeric complex is the signal that induces transcription activation of the downstream genes. After Mangelsdorf and Evans, 1995.

The examples of phosphorylase kinase and protein phosphatase I illustrate some important principles of regulation of enzyme activity by phosphorylation and dephosphorylation events. They clearly indicate how different signal transduction paths can meet in key reactions of metabolism, how signals can be coordinated with one another and how common components of a regulation network can be activated by different signals. The following principles are highlighted ... 

Fig. 10.1. Principle of signal transduction through intracellular protein kinase cascades. The intracellular protein kinase cascades are organized in modules composed in most cases of three proteinkinases and a scaffold protein. The modules process signals that are registered, integrated and passed on at the inner side of the cell membrane by central switching stations such as the Ras protein or the Rac protein. In the case of the MAP kinase pathway, the cascade includes at least three different protein kinases. Specific regulatory processes may take effect at every level of the cascade in addition, signals may be passed from the different protein kinases to other signaling pathways.

This chapter focuses on the approach we followed for developing a novel electrochemical sensor platform based on disposable polymer microchips with integrated microelectrodes for signal transduction. It presents the development of the so-called Immuspeed technology, which is dedicated to quantitative immunoassays with reduced time-to-results as well as sample and reagent volumes. Prior to presenting the specific characteristics of Immuspeed, the basic principles integrated in this platform are first presented and illustrated with reference to... 

Due to the proposed elementary steps of this sensing principle and the signal transduction from the surface reaction to a change of band structure and consequentially, to a change of resistance, as described in detail in (Weimar, 2002), the dependency of the sensor resistance from the concentration of analyte is logarithmic and the resistance change is dependent on the baseline value. In order to have a more transferable parameter for the characterization of sensor performance, the sensor signal S is defined as ... 

Investigation with the two optical transduction principles mentioned before confirmed the preferential enrichment of the S-enantiomer resulting in more than ninefold higher signals, which is the highest separation factor found for chiral separation on cyclodextrins up to now. The good agree-... 

Given the wealth of breakthrough-level work that has taken place over the past several years (in part detailed above), there seems little doubt that our overall understanding of the chemoreception has entered a robust period of growth and maturation. At first glance, it should be noted that the primacy of the conservation of general principles of olfactory signal transduction has now been... 

This chapter describes some of the principles and mechanisms underlying the primary processes of olfactory signaling, the chemo-electrical signal transduction. We will focus on molecular events that follow the interaction of odorants with olfactory sensory neurons, and leave aside perireceptor events including odorant... 

In principle, there is no limitation to the nature of the biological process or cascade, which can be influenced by (cyclic) peptides and their derivatives, and it should be emphasized that cyclic peptides and mimics derived thereof could be powerful instruments in modulating signal transduction. This is apparent, for example, from the interaction of cyclic peptides with SH2-domains involved in, among others, allergy, cancer and other diseases. 

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