23 min

Revealing how the cell uptakes sugar

Over half of our drugs impact proteins found on the cell membrane. These include the membrane proteins that regulate uptake of sugar by cells. Wallenberg Scholar David Drew is breaking new ground by adding to our understanding of the structure and function of transport proteins. 

David Drew

Professor of Biochemistry

Wallenberg Academy Fellow/Wallenberg Scholar

Institution:
Stockholm University

Research field:
Structure and function of membrane transport proteins

Some 20,000 different proteins have been mapped in humans. About half of them have the ability to bind other substances. A quarter can catalyze chemical reactions, and a much smaller proportion transport substances in and out of our cells.

About 14 proteins have been identified as transporters of sugar in human, although there are probably more to be discovered. But it is not known how they work at the molecular level, and why we even need so many different varieties of seemingly similar protein. These are questions to which Drew has devoted much of his career. 

“Essentially, we’re trying to understand the process by which we take up sugar. We want to understand how it happens, what the doors to a cell look like, and what causes them to open for some sugars but not for others,” Drew says.

The door to the cell can be said to be regulated by different buttons, which are affected by both the structure and movement of the proteins. To understand this complicated interaction, the atomic structure of each protein is being mapped. The structures are then modelled to provide atomic movies of the transport cycle.

“It’s very satisfying to watch the movies, because they are able to show a more tangible framework for how these minute machines actually work. However, they do not provide informational about the timescales for each state,” Drew says.

3D structures

Drew is aided by techniques such as crystallography and cryo-electron microscopy. Crystallography enables the researchers to make a three-dimensional image of a protein by directing an X-ray beam at the crystals. This reveals the position of the electrons in the outermost shell of the atom, which in turn reveals the external structure, making it possible to create a 3D image of the protein.

But this is a time-consuming process that requires large numbers of proteins, which are difficult to fabricate. Cryo-electron microscopy, a technique that has undergone significant improvements recently, offers a faster process, in which proteins do not need to be crystallized. Instead, they are quickly cooled to almost -200 degrees Celsius. The technique has a limitation, however, in the minimum size of molecules that can be studied. For the sugar transporters they are too small and so they need to be labelled with additional mass, such as by specific antibodies.

Although technological developments have had a great impact, Drew stresses the importance of methodological development and pooling of knowledge. 

“Technology is important, but the crucial factors are how we measure, analyze and then combine our insights. Arguably, the ability to combine the data from a number of different angles gives us a unique competence. Certainly I consider our research field as transport biology rather than structural biology per se.”

Unknown mechanism

The most recently published findings by the research team include a study of how malarial parasites take up sugar. Most cases of malaria are caused by a parasite capable of harvesting different sugars from our red blood cells. This ability has probably given the parasite an evolutionary advantage.

The team identified a previously unknown mechanism in which the protein establishes if a bound sugar will be transported or not. The findings attracted much attention, not least because no one had previously managed to capture the so-called “transition-state” of a sugar transporter.

“We were able to provide some long-awaited answers to fundamental questions. To understand how transport proteins work, you need to develop a complete picture of the transport cycle to be able to measure transport activity. These transport assays are very difficult to establish and these assays alone have taken us a number of years to work well.”

The researchers were also surprised by how little the difference is between glucose recognition by the parasite and that in the human brain. This finding may play a crucial role in developing drugs in the field of precision medicine.

“Traditionally membrane proteins have been targeted by drugs, but recent successes against transport proteins in the era of precision medicine are expanding the focus of Pharma.”

“The funding from Knut and Alice Wallenberg Foundation has been vital to our continued research and achieving results.”

In love with structural biology

Even as a student back home in New Zealand, Drew was fascinated by structural biology. By chance, he shared a lab with a team of biochemists who were mapping various protein structures.

“I was working as a master’s student in Forensic science, where I was developing a new system for DNA profiling for the criminal justice system. However, the lab I was assigned too was being renovated and I ended up using a lab bench in a structural biology group instead. Quite simply I feel in love with the biological insights that structures can provide”.

He had some Swedish acquaintances, who gave him the idea of studying for a PhD at Stockholm University. That was followed by a three-year stint as a postdoc at Imperial College in London. In addition to the structural work, it was there he continued to develop methods of producing and isolating membrane proteins that is now used in laboratories throughout the world. In 2009 he set up his own research team with a prestigious grant from the Royal Society.

“But my wife and I soon discovered the difficulties of starting a family in London. Stockholm and Sweden in general is a better environment if you have young children.”

A grant from Knut and Alice Wallenberg Foundation enabled him to continue his work in Stockholm. 

“Moving to Sweden and starting anew with a young family was an arduous process. But in the end, the research has benefited tremendously from the move from Imperial to Stockholm University. I’m very grateful to Knut and Alice Wallenberg Foundation for giving me this opportunity and the long-term support they have provided – it makes all the difference.”

Text Magnus Trogen Pahlén
Translation Maxwell Arding
Photo Niklas Björling, Mediabruket