 But that brings us back to this question. How do membrane proteins insert in membranes in the first place? Well, for that we're going to need to get back a little bit to the biology. You remember how I told you that we get the genome information from the DNA, it gets translated to messenger RNA, and then we have this ribosome. Let me draw the ribosome for you again. So the ribosome, we have the mRNA chain coming here, and then we have two parts of the ribosome. You have a small subunit and a large subunit. They look something like that. And then there is a hole here that we're basically going to start to create the protein chain, sometimes called the nascent chain, or this is the polypeptide. So here we get the tRNA coming with the amino acids. This is the mRNA chain. And that turns into a polypeptide, maybe a helix. Polypeptide. And you probably thought that this went straight out into water. I'm sorry, I lied a little bit to you there. This process occurs in a part of the cell called the ER, the endoplasmic reticulum. And the endoplasmic reticulum is actually a membrane. So I'm going to need to draw a small membrane for you here. So it turns out that the entire ribosome attaches itself to a membrane. That's very strange because you can't take that chain. Most proteins are going to be globular, right? Water soluble, they will never go through the membrane. No, they won't. So there is something else we need here. And what we're going to need is a, you probably guessed it, a protein. There is a protein here that at the time we might not have known anything about it. And that's called a translocon. Think of this as a channel. For now I haven't even shown you the structure. What would happen with a globular protein, a water soluble protein? This is on the special submembrane, the ER. And the water soluble ones, they will be pushed through here and pushed out, but this is not on the outside of the cell. This is in fact the inside of the cell. So here would be the cell, the cell inside. And this is a subpart of the cell. So a hydrophilic water soluble protein that would just lie out here from N to C terminus, and that it would fold roughly according to the ways we described before and that we're going to look more into later. But today we're talking about membrane proteins. So what happens with membrane proteins? Well, depending on how hydrophobic they are, magic happens here. And the magic consists of the protein ending up in the membrane, either N to C or N to C, which is a bit strange because it's the N terminus coming out first and then we have the C terminus. But sometimes it's able to turn here. What determines whether they end up out in the cell or in here is how hydrophobic they are. And that is because this translocon is not just a boring barrel, it has doors. The easiest way to show you that might be to show you the structure, I'll show you two structures. This was determined by Tom Rappaport, Fandenberg in particular, some 20 years ago almost. The translocon is a protein channel. It lets through the nascent chain and binds to the entire ribosome. But if you see here, between the green and the blue helix here, this is my two hands, but that barrel can open and it kind of breeds under normal circumstances. What happens is that the chain stops here and hangs around here for a while. And if the chain is now very hydrophilic, it doesn't matter when it opens because when this is opening up, we're just being exposed to lipids. And if I'm a hydrophilic protein, I hate lipids, I'm not gonna go there. And that will just make me continue out. Nothing special happens. But if this is a hydrophobic chain, what happens now when this protein breeds? I might, I will hang around here for a while and suddenly I'm exposed to a hydrophobic environment and then I can diffuse out in the membrane instead and then form a so-called membrane protein, a trans membrane helix. That is just one helix. And for an entire membrane to form, such as bacterial, sorry, such as bacterial rhodoapsin or something, I would need many helices. And in fact, that's how it happens. You get one helix at a time inserting and eventually all these helices will form a large so-called integral membrane protein. This is different from how globular proteins fold. Remember, globular proteins, they had this hydrophobic collapse of the entire protein. We're gonna look more into detail of folding models later. But for membrane proteins that are alpha helical, which is the vast majority of them, we're gonna have one helix at a time being folded already in the exit tunnel of the ribosome. They will come to the translocom. They will move out one finished helix at a time. And then these helices float around in this fluid mosaic model and then they will pack against each other. This is a bit beyond the scope of this particular class, but there was a famous result. The reason why we know this is true is Popo and Engelmann showed that they took a gene of Rodopsin, in fact, that has seven helices. And then they cut this gene in two halves. So one expressing three helices and the other one four. Now these things are gonna be inserted at different places, but what they showed is that they still got some functioning from this protein. So apparently the two halves must have diffused around in the membrane and found each other. So that's occasionally called the Popo Engelmann two-stage model. First insertion and then diffusion to find each other.