Caroline Speed; Week 6 MED1011; Biochemistry
To interpret signals a cell must have an appropriate receptor protein. In multicellular organisms signals may be local or distant. A signal transduction process is entire signalling process, from signal detection to final response. Involves a signal, a receptor, transduction and effects. Receptor activates intracellular signalling proteins, which activates effector proteins which act on the cell. A ligand is a signalling molecule that binds a receptor, binding of ligand causes receptor to change shape. Binds according to law of mass action and therefore binding is reversible (R + L <-> RL). Ligands can have plasma membrane receptors (large or polar molecules that cannot cross the plasma membrane, such as insulin) or cytoplasmic receptors (small/nonpolar molecules that can cross the plasma membrane, such as steroids).
Three well studied types of transmembrane receptors are ion channel receptors, protein kinases and G protein linked receptors. Ion channels are gates which are activated to open or close. An example is ACh receptor, there is a change in shape on binding the ligand. Some receptor proteins become kinases when activated, phosphate is transferred from ATP to protein, changing its shape or polarity. Sometimes it phosphorylates itself (autophosphorylation). Insulin receptors are kinase receptors, when insulin binds it dimerises and changes shape to reveal cytoplasmic active site, substrate is phosphorylated.
Seven spanning G protein linked receptors have ligands binding and changing shape of the protein on the cytoplasmic side. Exposes a binding site for the G protein. G protein also has a binding site for GTP, the GTP bound subunit separates and moves along the membrane until it finds an effector protein. Effector protein may catalyse many reactions, amplifying the signal.
Cytoplasmic receptors bind with proteins that cross the plasma membrane, receptor can change shape and enter the nucleus where it acts as a transcription factor eg steroids. Intracellular signalling molecules mediate between receptor and cellular response (second messengers and signalling proteins). Signal initiates series of events that eventually leads to a final response. In a protein kinase cascade signal transduction catalyses the phosphorylation of target proteins, is a cascade because each kinase phosphorylates the next. Ras is part of a cascade that influences cell division. MAPK at the end of the cascade phosphorylates AP-1 converting it to an active transcription factor.
Advantages to having many kinase steps are that each kinase can phosphorylate many other kinases, leading to amplification of the signal at each stage. Having many steps affecting different target proteins allows for a variety of responses by different cells to the same signal. Ras is like a protein switch, switched on by GTP binding and switched off by GTP hydrolysis.