Structural Biochemistry/Cell Signaling Pathways

Overview
Cell Signaling is an important facet of biological life. It allows cells to perceive and respond to the extracellular environment allowing development, growth, immunity, etc. Additionally, errors in cell signaling may result in cancer growth, diabetes. By understanding the processes that govern these pathways, scientists may understand the flow of information and transmission thereby allowing humans to treat diseases and grow tissues.

There are many different ways for cells to communicate with each other and the outside environment. They may communicate directly through juxtacrine signaling, over short distances through paracrine signaling and over large distances through endocrine signaling. Additionally, some cells require cell-to-cell contact in order for communication to occur. For this there are gap junctions which connect the cytoplasms of two cells together. In most cases, a molecule carries the signal from one cell and receptors on the other cell bind to the signal molecule thereby allowing communication. Afterwards, many pathways occur which ultimately trigger a cellular response.

Juxtacrine signaling are reactions when proteins from the inducing cell interact with receptor proteins of adjacent responding cells. The inducer does not diffuse from the cell producing it. There are three types of juxtacrine interactions. In the first type, a protein on one cell binds to its receptor on the adjacent cell. In the second type, a receptor on one cell binds to its ligand on the extracellular matrix secreted by another cell. In the third type, the signal is transmitted directly from the cytoplasm of one cell through small conduits into the cytoplasm of an adjacent cell.

Paracrine signaling is a form of cell signaling in which the target cell is near the signal-releasing cell. Some signaling molecules degrade very quickly, limiting the scope of their effectiveness to the immediate surroundings. Others affect only nearby cells because they are taken up quickly, leaving few to travel further, or because their movement is hindered by the extracellular matrix. Growth factors and clotting factors are paracrine signaling agents. The local action of growth factor signaling plays an especially important role in the development of tissues.

Endocrine signaling can be contrasted with two other modes of signaling: neural signaling and paracrine signaling. The different modes of signaling are schematized in the figure. A key difference is the distance that the regulatory molecule travels to reach its target. Neurons are connected to their target cells via synapses. A neurotransmitter crossing a synaptic cleft will travel between 10 and 20 nanometers. A paracrine will travel only a few millimeters before it is broken down, so it can only act on nearby cells. By contrast, hormones travel via the circulation to reach their targets, which may be multiple tissues that are far apart, and distant from the endocrine cells. Thus, hormones could be said to have systemic effects. Note that the timing involved in endocrine signaling also differs markedly from neural signaling. Neural signaling is brief and discrete, generally beginning and ending in less than a second. The timing of endocrine signaling is longer: the hormone takes more time to reach its target, the response of target cells takes longer, and hormones are more stable and capable of signaling over longer times.

Protein Acetylation (Histone Acetylation)
Protein acetylation is just one of the many examples of a cell signaling pathway. Protein acetylation plays a crucial role in the regulation of chromatin structures and transcriptional activity. Many of the transcriptional coactivators that are found in the body possess intrinsic acetylase activity while transcriptional corepressors posses deacetylase activity. Deacetylation or acetylation complexes both are associated with DNA-bound transcription factors that are in direct response to many signaling pathways. For example, histone hyperacetylation conducted by acetyltransferases are associated with transcriptional activity whereas Histone deacetylation is not. Histone acetylation stimulates transcription by remodeling of the higher order chromatin structures, that then weaken histone-DNA interactions and allow for binding sites for transcriptional activation complexes containing proteins that contain bromodomians which can then bind to acetylated lysines. Histone deacetylation on the other hand represses transcription through an inverse mechanism involving the assembly of higher order chromatin and exclusion of bromodomain-containing transcription activation complexes. At the organism level, acetylation plays many important roles in immunity, circadian rhythmicity and memory formation rather than just the Histone DNA interaction mentioned earlier. Because of these important roles protein acetylation has, it is now a favorable target in the drug design for numerous disease conditions.