30 November 2017

Publication in Nature Communications

Utrecht structural biologists discover surprising dual action mechanism for intracellular transport

Bert Janssen, sortilin

Researchers at Utrecht University have discovered how cells transport essential molecules such as proteins and peptides into their interior, for communication purposes and as a source of energy. Team leader, Dr. Bert Janssen explains how this insight is important to develop new drugs to combat a variety of diseases. On November 22, 2017, the team’s discovery was published in the renowned journal Nature Communications.

The cellular postal system

Our cells are intricate factories that need to maintain a careful internal and external balance to stay healthy. To protect itself from outside influences, the cell is surrounded by an impenetrable barrier, the membrane. To allow specific cargo that the cell needs to pass though, cells have an intricate postal system that can pick up proteins and nutrients outside, carry them across the membrane and deliver them inside (via a process called endocytosis).

Sortilin is a protein that has an important task in deciding which molecules can come in and which need to stay out. Like an antenna, sortilin sticks through the cell membrane and senses the world outside the cell. It can grab onto molecules the cell needs and transport these into the cell. Once it’s delivered its cargo inside, it returns to the cell membrane for another round of mail service.

When sortilin function is impaired, this can lead to heart disease, neurological disorders and metabolic disease. Researchers are eager to figure out how sortilin works, so that they can develop new drugs that can fix the problem. Until now, it was not known how this postmaster was able to carry so many different molecules into the cell without accidentally bringing in ‘bad’ ones, and how it released the molecules inside the cell.

“Our findings improve our understanding of this basic, yet important cellular mechanism.”

Shapeshifting proteins

Bert Janssen and his PhD student Nadia Leloup, of the Bijvoet Center for Biomolecular Research at Utrecht University have discovered how the sortilin transporter works. By studying the crystal structure of sortilin, the authors were surprised to find a dual action mechanism for delivering the molecular package inside the cell. When sortilin has transported a cargo molecule across the membrane into the more acidic internal environment of the cell, two changes are triggered: first, sortilin changes its physical shape, which loosens the binding between sortilin and its cargo. Second, the shapeshifted sortilin protein partners with another sortilin protein, popping the cargo molecule into the cell’s interior.

An avalanche of new question

Now that they know how sortilin works, they’re eager to take it to the next level. “Our findings open up a whole list of new questions,” says Janssen enthusiastically, “For example, do other transporter proteins work in the same way? And which possibilities does the dual action mechanism offer for specific drug targeting to treat disease?”

This work was performed in close collaboration with Philip Lössl and Albert Heck of the Biomolecular Mass Spectrometry & Proteomics, Utrecht University; Dominique Thies-Weesie of the Debye Institute for Nanomaterials Science, Utrecht University; and Martha Brennich at the European Molecular Biology Laboratory in Grenoble, France.

Image caption

Structural studies show that transported cargo (green oval) is released inside the cell because the more acidic environment triggers both a shape change and partnering of the sortilin transporter protein.

Publication

"Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release"
Nadia Leloup, Philip Lössl, Dimphna H. Meijer, Martha Brennich, Albert J. R. Heck, Dominique M. E. Thies-Weesie &  Bert J. C. Janssen
​Nature Communications 22 november 2017, doi:10.1038/s41467-017-01485-5