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Lecture 4

Lecture #4

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Darrel Desveaux

- We will look at the ABC transport proteins, then examples of ion channels that are a distinct category from transport proteins but also involved in moving small molecules across membranes and were going to look at how these ion channels contribute to the membrane potential in animal cells and also look at the different categories of ion channels in terms of gated ion channels. - Here is an overview of the different types of transport proteins that weve looked at so far. We looked at passive transport carried out by uniporters, active transport carried out by coupled transporters and particularly, the symporters and antiporters. Then we looked at ATP driven pumps, these also carry out active transport and in this case, it is primary active transport. - We also looked at the P-type ATPases that are phosphorylated, V type ATPases that mainly pump protons across membranes, F-type ATPases that are involved in ATP synthesis and then today were going to look at the final category of transport proteins: the ABC transporters. Dimerization of ATP binding domains Dissociation Conformational changes in transmembrane domains - Here is an overview of what ABC transporters look like. Theyre called ABC transporters b/c they have 2 ATP binding cassettes (domains). ATP binding cassettes would be ABC so it says domains but theyre also called ATP binding cassettes & in this overview, there are 2 ATP binding cassettes that are found on the cytosolic side of the membrane. Those can be the ATP binding domains, then there are two transmembrane domains in these proteins. - Theyre found in both bacterial and eucaryotic cells, the main difference b/w these 2 figures is that in bacterial cells, theyre mainly carrying out nutrient uptake from the environment & in eucaryotic cells, theyre typically carrying out the transport of toxins & waste products outside of the cell. This is not exclusively true, there are some bacterial ABC transporters that will also export toxins outside of the cell but one of the main functions is to uptake nutrients. - How is this done? One of the first steps is ATP binding. On the left is the original conformation of the ABC transporter, a small molecule, which could be a nutrient from the environment, will bind to the ABC transporter since this pocket here where the molecule binds is exposed to the outside of the cell. - Then the ABC transporter will bind ATP, there are 2 ATP binding domains, so this ABC transporter will bind 2 ATP molecules and this will induce a conformational change in this protein. This is important, again this is a transporter protein and one thing that unifies these transporter proteins is that they all undergo conformational changes as theyre transporting small molecules across the membrane. - You have ABC transporter there, ATP binds & induces a conformational change, then the ATP is hydrolyzed to ADP & that exposes this small molecule now to the cytoplasm of the cell & it will be released in the cytoplasm. That is how basically the overview of how ATP binding & ATP hydrolysis induces this conformational change. - Recap: ATP binding induces the dimerization of ATP binding domains, so you can see that those are the two ATP binding domains, they arent associated with each other, when they bind to ATP, they dimerize together inducing a conformational change. Then the ATP is hydrolyzed shown in the slide and this causes the dissociation of the small molecule from the ABC transporter and ATP binding and ATP hydrolysis induces these conformational changes in the transmembrane domains as shown in the slide. This exposes the binding site of small molecules, it goes from being exposed to the extracellular space and then the conformational change induces it to be exposed to the cytosol of the cell. The substrate binding site goes from being exposed on one side of the membrane, to the other and that induces transport. - Now when the eucaryotic ABC transporter that would be exporting toxins out of the cell, the original conformation would have substrate binding sites on the cytosolic side, the small molecule can bind, ATP binding to the ABC transporter would induce dimerization of these domains, and induce a conformational change of the transmembrane domains. ATP hydrolysis would induce the dissociation of the small molecule now in this case to the outside of the cell. Sequester toxins removed by leaf shedding - In bacteria, these ABC transporters are important for importing nutrients into the cell but theyre also involved in exporting toxins and they can actually be very important in developing antibiotic resistance in bacteria since some of these ABC transporters can actually transport antibiotics outside of bacterial cells and then these bacteria can become more tolerant to antibiotics. So they can be involved in import and export in bacteria. - In plants, they are involved in transporting toxins from the cytosol to the vacuole & this is done to store these toxins in the vacuole & then they can be removed by leaf shedding. So the toxins become sequestered in the vacuole by the ABC transporters & then plant can get rid of these toxins by shedding its leaves. - In animals, theyre also used to export natural toxins & also waste products & also drugs. One of the very famous examples is called multi-drug resistant protein 1 or MDR1. This protein can export drugs from cancer cells and there is over-expression of MDR1 in numerous types of cancers and this can lead to resistance of these cancers to chemotherapeutic drugs. Since the cancer overproduces these ABC transporters called MDR1, the chemotherapeutic drugs are pumped out of the cancerous cell & are much less efficient at treating cancer. - This is a diagram of MDR-1 and normally it's expressed in liver, kidney and intestinal cells. It is involved in excreting natural toxins or waste products into the bile, urine or feces but it is also able to export drugs so its ability to excrete toxins also make it capable of exporting drugs and it is overexpressed in many cancer lines following treatment with chemotherapeutic drugs. This leads to resistance of cancers to chemotherapy. - ABC transporters play very important roles in numerous drug resistance, antibiotic resistance and were not going to cover it in detail but it is also the mutation of ABC transporters that can lead to cystic fibrosis. So they play important role in diseases and drug resistance. That is as far as we will cover the transporter proteins, so we just finished the ABC transporters and now were going to move onto a second category of proteins that move small molecules across membranes: channel proteins. All channel proteins carry out passive transport and unlike transporter proteins, channel proteins do not undergo conformational changes as theyre transporting their small molecules across the membrane. Weaker interactions with solute Faster transport by channels Several molecules pass through when open - Here is a diagram of a channel protein and basically what it does is it creates a hydrophilic pore across the membrane, so the grey is the lipid bilayer, then there is the channel protein in green and it creates this hydrophilic pore through which these small molecules can cross the membrane. - Most channel proteins are selective meaning they will transport one particular type of ion, so youll have potassium channels, youll have sodium channels, youll have calcium channels and they will be specific for that type of ion. Were going to go mainly into different ion channels. These are the major examples were going to cover. - They all carry out passive transport, now they create a weaker interaction with their solutes than transporter proteins, so youll recall that the glucose uniporters also carried out passive transport but they bind to one molecule of glucose, undergo a conformational change, release the glucose on the other side of the membrane and then change conformation back to be able to transport another molecule of glucose. You can see that that it would be much slower than transporting a molecule just allowing it traverse the membrane through a channel. They have much weaker interaction with the solute, and they carry out
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