Kevin Ahern's Bite-Sized Biochemistry #18: Signaling
1. Contact - [email protected] 2. Kevin's lectures with The Great Courses - https://www.thegreatcoursesplus.com/b... 3. Kevin's Lecturio videos for medical students - https://www.lecturio.com/medical-cour... 4. Course materials at https://kevingahern.com/biochemistry-... 5. Course video channel at • Kevin Ahern's Bite-Sized Biochemistry #1: ... 6. Metabolic Melodies at https://teeheetime.com/category/lyric... 7. Kevin's Free Biochemistry books - https://kevingahern.com/biochemistry-... 8. Kevin's Pre-med Audio course on Listenable - https://listenable.io/web/courses/143... Lecture Highlights Carbohydrates III 1. All N-linked glycoproteins have the same core of five carbohydrate residues. N-linked glycoproteins have glycosylation (addition of carbohydrate residues) occurring in the endoplamic reticulum and Golgi complex of the cell. O-linked glycoproteins have glycosylation occuring only in the Golgi complex. 2. Movement of modified proteins from the endoplasmic reticulum to the Golgi complex allows for additional carbohydrate modifications to occur, followed by targeting to 1) the cell membrane, 2) release from the cell, or 3) the lysosome. 3. Mannose-6-phosphate (M6P) is put on glycoproteins to target them to the lysosome (I incorrectly said Golgi apparatus in class). Deficiency of the enzyme that puts M6P onto glycoproteins leads to I-cell disease. 4. Specific carbohydrate residues on the surface glycoproteins of blood cells are binding targets for proteins on the surface of flu viruses. Anti-flu drugs like tamiflu act by inhibiting the action of the neuraminidase. Signaling Highlights 1. Signaling is essential for cells in multicellular organisms to communicate with each other. 2. The beta-adrenergic receptor, works as follows. A ligand, such as epinephrine is released into the bloodstream in response to a stimulus. This molecule is the first messenger. When it arrives at the target cell, it binds to the receptor, causing the receptor to change shape slightly, changing the interaction of the receptor with a G protein (see below) to activate it. The activated G protein, in turn, activates the enzyme adenylate cyclase, which, in turn, begins to synthesize cAMP. cAMP is a so-called second messenger, which acts by binding to Protein Kinase A (PKA) to activate it. 3. Phosphorylation of proteins known as transcription factors can activate or inactivate them. When activated they will turn on transcription of specific genes in the DNA. 4. Thus, signaling can have rapid effects (controlling enzyme activities) or slower effects (controlling gene expression by controlling transcription) 5. Receptors of the first messenger have similarity in structure, consisting of a polypeptide chain that spans the cell membrane 7 times. Such proteins are called 7TM proteins. 6. G proteins bind guanine nucleotides (GDP and GTP). Cells have 'families' of G protein complexes arising from the fact that there are multiple, slightly different versions of the individual subunits in the genome and these can be paired in many ways. The alpha subunit binds to GDP or GTP. When the alpha subunit is bound to GDP, it also binds the beta and gamma subunits. The G protein complex is thus inactivated. When the beta-adrenergic receptor binds its ligand, the receptor stimulates the 'loading' of GTP onto the alpha subunit, displacing GDP in the process. Upon binding GTP, the alpha subunit dissociates from the beta and gamma units. The alpha subunit is then free to bind other target proteins and is thus 'active' when bound to GTP. 7. G proteins have an enzymatic activity that slowly breaks down GTP to GDP within the alpha subunit. This activity is very important because it ensures that the G protein will not be left in the 'on' state permanently. When the alpha subunit is bound with GTP, it can bind to adenylate cyclase and activate it. 8. Cells have two ways of turning off the beta adrenergic receptor. The first involves simple dissociation of the epinephrine ligand from the receptor. This leaves the receptor in the 'off' state. The second method involves phosphorylation of the receptor by a receptor kinase. The phosphorylated receptor is then bound by the protein called beta-arrestin that binds the receptor and inhibits the activation of G proteins. 9. cAMP in cells acts on a kinase known as Protein Kinase A (PKA).
