Membrane Proteins

Molecular Biologist Richard Henderson on new protein structures, experiments with electron cryomicroscopy, and aquaporin

videos | May 31, 2018

Membrane proteins are the most important component in membranes, all the various types of membranes such are in and around cells. The two components of a membrane are the lipids and the proteins. The proteins essentially do all of the difficult and most important tasks. Originally it was thought that these proteins – this is a Singer and Nicolson model of the membrane – are simply floating around in a sea of lipids that didn’t do very much. Now it’s actually known that there are positive functions for some of the lipids. For the purpose of this talk I’m going to focus on the proteins, which actually carry out many of the individual tasks, hundreds of thousands of different tasks in the cell membrane. Each one of them, different membrane protein has a different function and carries out different tasks in the membrane: transporting small molecules in and out of the membrane, transporting big molecules like proteins in and out of the membrane, signaling from the inside to the outside of the cell, or from the outside to the inside of the cell. So, they have a very important role and understanding how proteins are built, their structure and how they function in doing their different tasks is the key to understanding how membranes work and how cells work.

It turned out – this was their hypothesis – that soon after this the structure of myoglobin was solved experimentally, and it was shown to be composed entirely of alpha-helical stretches, exactly the alpha helix with a heme group, which is the red oxygen binding pigment in the center of it. A little bit later other structures came along lysozyme, chymotrypsin. Now there are hundred thousand sets of coordinates deposited in the protein data bank with tens of thousands of different protein structures, and they all have alpha helix and beta sheets in them. That’s all of proteins. Membrane proteins in the 70’s were unknown. Many people were wondering how it would be. In a membrane you have this lipid bilayer, it’s a hydrophobic barrier between the inside and outside of the cell, so you have to get protein molecules either on the lipid or particularly extending through the lipids – transmembrane proteins.

One idea was that you cannot have the parts of the protein that need to interact with water interacting with a lipid bilayer. That means that in a protein molecule you have a polypeptide chain, there are components of the polypeptide that must be solvated by water. So, you have a peptide bond, you have an NH-group, and you have a carbonyl group. So, you have the peptide bond with NHCO and these are the two moieties that are involved in alpha helix and beta sheet. If you have a beta-sheet, all the hydrogen bonds are satisfied inside the beta-sheet. If you have an alpha helix, all these hydrogen bonds between the NH and CO are in the alpha helix. It was a reasonable hypothesis.

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Most recently the electron cryomicroscopy method has been improved technically by better microscopes and detectors. Now you can determine structures of membrane proteins and other proteins without ever making a crystal, without doing electron crystallography, without doing x-ray crystallography. Now there are increasing numbers of quite important membrane protein structures being determined by these newer methods. Now we have a situation where in the protein data bank, which is the depository for all the protein structures and nucleic acid structures, and ribonucleoprotein structures – all the different proteins and structures in biology – there are now a hundred thousands of these deposited. It would take you a long time just to look at them all and of these one hundred thousands probably a few thousand are membrane protein structures. Still we may have knowledge of perhaps the three-dimensional structures of half the proteins in the world, either as a 3D-image of the structure itself or some related, similar, homologous structure.

In summary then, having started with nothing, we now have a knowledge of thousands of different membrane protein structures: beta barrel structures, alpha-helical structures, and then there are a few that are hybrids of the two, and then there’s just the occasional special membrane protein, for example aquaporin, which has a function of allowing water molecules to pass through all cells, but particularly in the red blood cells, controls the size and osmotic pressure. That has a very special arrangement of the polypeptide, where one of the strands of the protein goes in and turns around halfway through the membrane and comes back, and a similar one from the other side. There are perhaps a very small number of ultra special membrane proteins that do not fit into these categories. That’s because they have a particular function. I would say now we have a really excellent idea about membrane protein structure and this knowledge permeates the thinking of all the people in biology who are studying different aspects of biology.

Molecular biologist and biophysicist, MRC Laboratory of Molecular Biology, Cambridge
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