Protein, proteins modulation

The intracellular messengers are diffusible signal molecules and reach their target proteins mostly by diffusion. Close spatial proximity of the signal components, as achieved for transmembrane receptors and their effector proteins with the help of membrane anchoring or with specific protein-protein modules (see Chapter 5, Chapter 8), is not necessarily required for this type of signal transduction. 

The occurrence of multiple protein modules is characteristic of adaptor proteins these mediate different protein-protein interactions and can thus bring about cross-linking of signal proteins. Protein modules frequently found in adaptor molecules are SH2 and SH3 domains, PTB domains and PH domains. Furthermore, adaptor proteins may be covalently modified by N-myristoylation and Tyr-phosphorylation. Figure 8.24 shows the schematic composition of some important adaptor molecules. 

Small protein modules form adaptors for a signaling network... 

Pawson, T. Protein modules and signaling networks. Nature 373 573-580, 1995. 

Now that many thousands of proteins have been sequenced (more than 100,000 sequences are known), it has become obvious that certain protein sequences that give rise to distinct structural domains are used over and over again in modular fashion. These protein modules may occur in a wide variety of pro-... 

FIGURE 6,37 Ribbon structures of several protein modules utilized in the construction of... 

FIGURE 6.38 A sampling of proteins that consist of mosaics of individual protein modules. The modules shown include 7CG, a module containing 7-carboxyglutamate residues G, an epidermal growth-factor-like module K, the kringle domain, named for a Danish pastry ... 

FIGURE 23.22 The metabolic effects of insulin. As described in Chapter 34, binding of insulin to membrane receptors stimulates the protein kinase activity of the receptor. Subsequent phosphorylation of target proteins modulates the effects indicated. 

The ankyrin repeat motif is one of the most common protein-protein interaction domains. Ankyrin repeats are modules of about 33 amino acids repeated in tandem. They are found in a large number of proteins with diverse cellular functions such as transcriptional regulators, signal transducers, cell-cycle regulators, and cytoskeletal proteins. 

Another example is a recently discovered second mode of action by which nuclear receptors modulate transcription. In contrast to DNA-binding-dependent mechanisms, cross talk refers here to gene regulation by protein-protein-interaction of nuclear receptors with other transcription factors, such as AP-1 or NF-kB. Consequently, the nuclear receptor acts as a corepressor or coactivator of transcription. 

Interferon beta-la (AVONEX , Rebif ), interferon beta-lb (Betaferon ), and interferon beta (Fiblaferon ) are applied in multiple sclerosis to reduce both frequency and severity of disease incidents and for the treatment of severe viral infections. In multiple sclerosis, DFN- 3 proteins modulate the destruction of myelin in the cause of the autoimmune reaction. 

Heptahelical domains are protein modules found in all known G-protein coupled receptors, made up of seven transmembrane helices interconnected by three extra and three intracellular loops. For most G-protein coupled receptors activated by small ligands, the binding site is located in a cavity formed by transmembrane domains 3, 5, 6 and 7. 

Clark MJ, Harrison C, Zhong H, et al Endogenous RGS protein action modulates mu-opioid signaling through Galphao effects on adenylyl cyclase, extracellular signal-regulated kinases, and intracellular calcium pathways. J Biol Chem 278 9418-9425, 2003... 

FIG. 20 DNA duplex 20 used for studies regarding the protein-modulated DNA electron transfer. Methyltransferase M.Hhal is capable of binding to the shadowed recognition site between two oxidizable 5 -GG-3 sites (outlined letters). The complementary strand of the duplex contains the Rh intercalator, [Rh(phi)2bpy ], at its 5 end, which can function as a photooxidant. (Adapted from Ref. 168.)... 

Benfanati, F, Onofri, F and Giovedi, S (1999) Protein-protein interactions and protein modules in the control of transmitter release. Phil. Trans. Roy. Soc. Lond. B 354 243-257. 

It is perhaps not surprising that DA produces such mixed effects. The Di receptor is primarily linked to the activation of adenylate cyclase and then protein kinase A. The response to its activation will therefore depend on the ion channels and other proteins modulated by the kinase which can vary from one neuron to another. Since the D2 receptor is not so closely associated with just one G-protein, this gives it the potential for even more effects (see Greenhoff and Johnson 1997). 

Takahashi, T, Kajikawa, Y and Tsujimoto, T (1998) G-Protein-coupled modulation of pres5maptic calcium currents and transmitter release by a GABAg receptor. J. Neurosci. 18 3138-3146. 

Mehler EL, Fuxreiter M, Simon I, Garcia B-Moreno (2002) The Role of hydrophobic microenvironments in modulating pKa shifts in proteins. Proteins 48 283-292. 

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