q&more
My watch list
my.chemie.de  
Login  

News

How enzymes build sugar trees

Findings could accelerate development of new, protein-​based medications

ETH Zürich / Joël Bloch

ALG6 is made up of a structurally conserved (green) and a structurally variable (red) module. The antigen-​binding fragment (purple, cyan) that attaches to the enzyme made it possible to study the latter using cryo-​EM.

02-Mar-2020: Researchers have used cryo-​electron microscopy to elucidate for the first time the structure and function of a very small enzyme embedded in cell membranes. This enzyme builds complex sugar trees that are subsequently attached to other membrane proteins. The findings could accelerate the development of new, protein-​based medications.

Many of the membrane proteins in eukaryotic cells are decorated with complex sugar trees called glycans. In addition to being extremely diverse, these sugar trees serve as a way to identify the respective organism, a cell type or its stage of maturity. For instance, the various blood groups in humans feature different glycans.

Complex sugars that are attached to lipids form a special class of glycans. In biology, these are known as lipid-​linked oligosaccharides, or LLOs. LLOs are made up of a fat molecule embedded in the cell membrane and a sugar structure that extends either into the lumen of cell organelles or extracellularly.

Researchers from ETH Zurich, the University of Bern and the University of Chicago have now elucidated the structure of one of the enzymes responsible for the formation of LLOs. Their study has just been published in the latest issue of the journal Nature.

Modular protein architecture

The enzyme in question, known as ALG6, belongs to a superfamily of enzymes that the researchers call glycosyltransferases of the category C. Embedded in cell membranes, these link simple sugar molecules with other sugars in order to build sugar trees. They also link sugar molecules with proteins. In this capacity, glycosyltransferases play several key biological roles in all kinds of organisms, ranging from bacteria and fungi to highly developed mammals.

This enzyme superfamily had been a long-​standing mystery to biologists because its individual members share hardly any structural motifs. The only things they do have in common is that they are membrane proteins that transfer sugars from one molecule to another, and that the sugars used for this transfer are always attached to lipids.

Based on the structure of ALG6, the group led by ETH Professor Kaspar Locher has now discovered that the members of this enzyme family have a modular design. Their research indicates that ALG6 and its relatives are made up of two modules: one whose structure is preserved during development, and a second, structurally variable module.

“We believe it’s this modular design that helped these enzymes to evolve in different directions and, in turn, adapt to a large variety of different substrates,” says Joël Bloch, an ETH doctoral student and the lead author of the study.

The findings finally explain the mechanism behind the enzyme family. “Our study has far-​reaching implications for cell biology and for the production of therapeutic substances based on glycobiology,” Bloch explains. These insights will be especially valuable in antibody engineering, which is currently of great interest to the pharmaceutical industry. They will also benefit the production of customised glycans in general, which are important for therapeutic proteins such as antibodies.

A record in cryo-​electron microscopy

The researchers also see their results as a breakthrough in determining the molecular structures of proteins using cryo-​electron microscopy (cryo-​EM). In 2017, the Swiss researcher Jacques Dubochet received the Nobel Prize in Chemistry for his contribution to this groundbreaking technology, which has since become the method of choice for the structural elucidation of large molecular complexes.

Determining the structures of small proteins at high resolution, especially those embedded in membranes, had not been possible using cryo-​EM because measurements taken of particles below a certain mass do not permit precise structural calculations.

Working together with a research group from the University of Chicago, the ETH team have now found a solution to this problem. In collaboration with the Chicago-​based researchers they produced a synthetic antibody that binds to ALG6. This antibody increased the mass of the ALG6 enzyme such that its structure could be determined in high resolution using cryo-​EM.

“With our approach, we currently hold the world record for the highest structural resolution obtained for a membrane-​bound complex of this size,” Locher says with a hint of pride. He explains that these advances with cryo-​EM will enable many other scientists to elucidate the structures of small membrane proteins: “Our approach paves the way for the scientific community to make rapid progress in the study of membrane proteins associated with a wide range of diseases.”

A chemo-​enzymatic toolbox

As if that were not enough, the ETH researchers, in collaboration with chemists from the University of Bern, have now developed methods for synthesising highly complex lipid-​linked oligosaccharides in the lab – something that had not been possible with conventional synthesis methods in organic chemistry.

As a result, the researchers have now gained new insight into the essential cellular pathway of LLO biosynthesis, helping them explain how cells build complex glycans. “This marks a milestone in glycobiology that could form the basis for many glycobiologists’ future research and for the production of glycoproteins,” Locher says.

Original publication:
Bloch J et al.; "Structure and mechanism of the ER-​based glucosyltransferase ALG6"; Nature; published online 26th Feb 2020.

Facts, background information, dossiers

  • cryo-electron microscopy
  • enzymes
  • membrane proteins
  • glycans
  • oligosaccharides
  • glycobiology

More about ETH Zürich

  • News

    Lighting the path for cells

    ETH researchers have developed a new method in which they use light to draw patterns of molecules that guide living cells. The approach allows for a closer look at the development of multicellular organisms – and in the future may even play a part in novel therapies.  Highly complex organis ... more

    A new biosensor for the COVID-19 virus

    A team of researchers from Empa, ETH Zurich and Zurich University Hospital has succeeded in developing a novel sensor for detecting the new coronavirus. In future it could be used to measure the concentration of the virus in the environment - for example in places where there are many peopl ... more

    Printing complex cellulose-based objects

    Researchers from ETH Zurich and the Swiss Federal Laboratories for Materials Science and Technology (Empa) have set a new world record: they 3D printed complex objects with higher cellulose content than that of any other additively manufactured cellulose-​based parts. To achieve this, they ... more

  • q&more articles

    Analysis in picoliter volumes

    Reducing time, costs and human resources: many basic as well as applied analytical and diagnostic challenges can be performed on lab-on-a-chip systems. They enable sample quantities to be reduced, work steps to be automated and completed in parallel, and are ideal for combination with highl ... more

    Investment for the Future

    This is a very particular concern and at the same time the demand placed annually on Dr. Irmgard Werner, who, as a lecturer at the ETH Zurich, supports around 65 pharmacy students in the 5th semester practical training in “pharmaceutical analysis”. With joy and enthusiasm for her subject sh ... more

  • Authors

    Prof. Dr. Petra S. Dittrich

    Petra Dittrich is an Associate Professor in the Department of Biosystems Science and Engineering at ETH Zurich (Switzerland). She studied chemistry at Bielefeld University and the University of Salamanca (Spain). After completing her doctoral studies at the Max Planck Institute for Biophysi ... more

    Dr. Felix Kurth

    Felix Kurth studied bioengineering at the Technical University Dortmund (Germany) and at the Royal Institute of Technology in Stockholm (Sweden). During his PhD studies at ETH Zurich (Switzerland), which he completed in 2015, he developed lab-on-a-chip systems and methods for quantifying me ... more

    Lucas Armbrecht

    Lucas Armbrecht studied microsystems technology at the University of Freiburg (Breisgau, Germany). During his master’s, he focused on sensors & actuators and lab-on-a-chip systems. Since June 2015, he is PhD student in the Bioanalytics Group at ETH Zurich (Switzerland). In his doctoral stud ... more

q&more – the networking platform for quality excellence in lab and process

The q&more concept is to increase the visibility of recent research and innovative solutions, and support the exchange of knowledge. In the broad spectrum of subjects covered, the focus is on achieving maximum quality in highly innovative sectors. As a modern knowledge platform, q&more offers market participants one-of-a-kind networking opportunities. Cutting-edge research is presented by authors of international repute. Attractively presented in a high-quality context, and published in German and English, the original articles introduce new concepts and highlight unconventional solution strategies.

> more about q&more

q&more is supported by:

 

Your browser is not current. Microsoft Internet Explorer 6.0 does not support some functions on Chemie.DE