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Lecture 22.docx

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University of Toronto Scarborough
Biological Sciences
Dan Riggs

Lecture 22 – Signal transduction 2- G proteins/lipid derived signaling molecules/second messengers. G proteins are called that because they bind to guanine nucleotides, either to GTP or GDP. We will also talk about lipid signalling and second messengers. There are a lot more acronyms in this lecture so there's a lot of memorization needed. Figure 15 – 2. What you see is the generalized signaling pathway. At the top is a signaling cell or an external signal that the cell finds itself in the presence of. This extracellular signaling molecule is often referred to as a first messenger or as the. Regardless of what it is, either hormone or small molecule or ion, this takes place at the cell surface. There are a couple of different types of receptors that exist. Keep in mind that a cell can only perceive a signal and it contains a receptor for that specific type of signal. The signaling ligand and the signal has to match a receptor that exist usually at the cell surface as part of the plasma membrane. Today we will talk about how the receptor gets activated and the series of signaling events that take place in order to generate the response which can be a variety of different things. What we will see today is that a single signal can generate a variety of different responses in different tissues. Most STP or signal transduction pathways, rely on changes in the phosphorylation states of the molecules. Kinases are enzymes which phosphorylate target molecules. This action is undone by phosphatases which take off phosphate from their target molecules. As seen in the case of cyclin dependent kinase, some targets like CDK are active when they are phosphorylated in a certain way and sometimes they are inactive when they are phosphorylated. Others can only be active when they are dephosphorylated or phosphates exist only in certain positions in the molecule. The utility of this provides a very quick switch in order to take a protein that has already been made, so you don't have to go through the trouble of activating gene expression or getting RNA polymerase to do the job, making and processing the primary transcript, and exporting it to the cytoplasm, associating with ribosomes to make a protein. No. You already have the protein made and putting on or take it off a phosphate provides a quick switch to regulate protein activity. Figure 15 – 3 shows an example where a protein kinase cascade occurs. If we start at the top, there is protein kinase 1 and by some unknown means, it became active in some way. It looks around for its target molecule and it comes in contact with protein kinase 2. This one is not active and can only be activated if protein kinase two on the left is in active and can only be activated if the protein kinase one puts a phosphate group on to protein kinase too. The same thing happens with in active protein kinase three which he needs one or more phosphate groups from protein Kinase two to become active. One of the targets of protein kinase three could be a transcription factor that is in active and studies have shown that one transcription factors have been phosphorylated in a certain way, this changes their structure such that a new clear localizations Signal is exposed and the transcription factor can move from the cytoplasm to the nucleus for example and exert its effect. This is a generic version of how these false correlations event might occur in a cascade to change in gene expression. Question is what controls the phosphorylation of phosphatases earlier than that. One of the things that is an integral piece of the puzzle of signaling cascades are referred to as G protein. The G stands for Hueneme nucleotide binding proteins or GTP binding proteins. These are often membrane-bound but there are also monomeric G proteins which we will talk about next week. g proteins transduce the signal from and activate or a receptor to something called a effector molecule which is usually an enzyme. Figure 15 – four shows what is going on strategically at the cell surface. The double lipid bilayer is the plasma membrane. There is a receptor with a number of membrane spanning domains so there is an extracellular domain on the outside of the cell which abides the ligand or the signaling molecule. Then when the ligand binds, The receptor will change its structure to allow it to bind to the G protein complex. In this sense, the G protein is not a single molecule but actually a combination of in Alpha Beta and gamma subunits as a trimer. These subunits are different and therefore they referred to as hetero trimers. What you see from this diagram is that alpha and beta and gamma trimer are attached to fatty acid groups which is embeds them into the inner surface of the Plasma membrane. This helps to anger them there and strategically positioned them in the same domain as other receptors and that defector. I'll Faught is bound to GDP or GTP which is the business and of the G protein. X This is the subunit that is going to transduce the signal further downstream and it possesses GT PAs activity. That is it can bind to a GTP molecule but sometime later it is going to exert the GTP ace activity to cleave GTP to GDP to stop the signal when pathway. The effectors of that become active are usually enzymes. There are A variety of different types of them and there are two of them in particular that we will talk about today what your enzymes called Aydin a little cycleways and a variety of different enzymes called Phospho ligases These produce second messengers. Figure 15 – five is the most important figure from today's lecture. It shows the pathway of a cell on where the plasma membrane is in blue as the receptor is green. It shows through the point where there is no bound signaling molecule to the binding of the signaling molecule to the series of events that take place through the G proteins to activate the effector And signal other downstream events. The first step is the receptor within extracellular domain which is it available to sense or binds to the lake end or signaling molecule. It hasn't intracellular face which allows it to Interact with a G protein. When the light and comes in, the receptor binds to it and that allows the receptor to binds to the trimeric G protein that is in the GDP downstate. Upon the binding of the light again to the receptor, the cytoplasmic side of the receptor changes its structure in such a way that allows it to binds to the G protein. So the drawing should be changed a little bit to show that after the Finding Oakhurst, the intracellular domain has changed its structure and is complementary to the G protein. Instep to what is going to happen is that G Protein activation will take place. I'll fall loses the GDP and exchanges it for a molecule of GTP. This puts Alfara in the active form. I'll step three the Alpha subunit dissociates From its partners, and moves along the membrane until it comes in contact with the purple molecule called the effector molecule. In this particular example, the effector is I didn't allow cyclase. I done I will cyclase is an enzyme that takes ATP and make a cyclic structure out of it. You lose two of the phosphates and make cyclic ANP. This is a powerful second messenger. Now you have generated cyclic A&P. And step four. Now this is an Aubert at an opportunity to amplify the original signal. The original signal was one molecule of the signal first messenger Bound to the receptor. After doing this.however, this is the enzyme so it can potentially take 1000 molecules of ATP per second and change them into cyclic A&P. Now you amplify the signal from one molecule to 100 Molecules or 500 molecules. Quickly building up the concentration of this potent second messenger. Now it's.5 after sometime, the Alpha subunit GT PAs activation activity it's going to be activated. This will Cleavant GTP into GDP. When this happens two things occur. First, the G protein subunit reassociate with one another, That is alpha gets back with beta and gamma and secondly, the addenda will cyclase is no longer being stimulated. This is the beginning of terminating the signaling response. Now at step seven, although the internal signal is being turned down or began to be turned off, at the cell surface, the original signaling molecule might still be in place. But it may be inappropriate for signaling to continue. What tends to happen at that point is about the receptor becomes phosphorylated itself. There is something called G arcade which stands for G protein receptor kinase and it puts one more phosphate group onto the intercellular side Of the receptor and I'm basically that eventually creates a binding site for a series of molecules called a Rustins. Instep eight when a Rustins find, they desensitize the receptor. The signal is still there but they change the receptor in such a way that it cannot communicate with the G protein anymore and therefore the G proteins is not transducing the signal. The G proteins are not activated. What may happen in this situation are a couple of different things. First is that the receptor is often internalized by endocytosis, taking to membrane vesicles, and and might be turned into a lysosome and destroyed, Other times the receptor is taken in by endocytosis and the phosphates are taken off and the vesicle then blinds with the plasma membrane and delivers the receptor back to the plasma membrane now in the active state. This way it saves the molecule energy from re-creating a receptor that it needs. Figure 15 – 19 is a complex figure that is been broken down into pieces. Judaize, GDF gefs and gAPs are a variety of small molecules that can influence g protein activity. The GDI's stand for all I need nucleotide dissociation inhibitors. It guanine nucleotide is a GTP or G DFP. Dissociation means to release one from the other and these are molecules that inhibit that action. Operationally, at some time of the cell, there is a G protein that is inactive because it is bound to GDP. The GDI molecule comes in and find interacts with this complex and keeps the complex in the GDP bound form. That is it keeps GDP from being released which keeps the G protein and I'm in active state. This takes place and you are depending on GTP bound molecules signaling to downstream effectors and other components is interrupted. GEF stand for guanine nucleotide exchange factors. This does the opposite as G deice. Operationally, that GEF comes in with an interactive G protein. It binds to the protein and promotes a GTP binding Which is an exchange of GTP with GDP which will activate the G protein. Then the GEF will dissociate which enables the active G protein to interact with the target protein and activates It for the signal to be transduced. GAAP stand for GT PAs activating proteins. The active G protein typically has an alpha Subunit that is the business end of the subunit. Of the molecule. It possesses the GT PAs activity but it may not be exerted act a certain time. The guy protein that binds to this enhances or activates This activity and then GTP is hydrolyzed to GDP. This means that the G protein will become active because it is a GDP bound state signaling to other downstream components halts. Importantly, the concentration of the gaps and what type of action they have on certain G proteins that are present, this is determines the duration of the signal. The clock with the switch off means how many molecules With GTP ace activating proteins are present? How active are they? On a particular substrate? And that determines how long the G protein is going to be in its active form. That controls the duration of the signaling pathway. How are they important? Look at the acumen perspective on page 612. This tells us that there are over 2000 G protein coupled receptors in humans. The human genome him has around 25 to 30,000 genes. 2000 of the 25,000 so quite a large number of a percentage of genome is devoted to making G protein coupled receptors because of coarse different cells types exist, Each response to different types of signals, some cell types have a variety of different types of receptors, other Celtics have fewer receptors and the importance in terms of our everyday life aren't things like over about a third of prescription drugs in someway Act in G protein m
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