Nav: Home

Molecular scissors stabilize the cell's cytoskeleton

June 24, 2019

Researchers at the Paul Scherrer Institute PSI in Villigen, Switzerland, have for the first time elucidated the structure of important enzymes in human cells that alter essential building blocks of the cellular cytoskeleton. This reveals the missing part of a cycle that regulates the build-up or breakdown of supporting elements of the cell. The enzymes investigated work as molecular scissors and can be involved in the development of various diseases, for example, cancer and diseases of the nervous system. Their structural elucidation provides approaches for the development of specific inhibitors and perhaps new therapies. The researchers gained detailed insights into the structure of the enzymes with the help of the Swiss Light Source SLS. They have now published their results in the journal Nature Structural & Molecular Biology.

They give human cells their shape, play a decisive role in cell division, and help to transport substances through the cell: the so-called microtubule filaments. The tasks they perform are of such central importance for life that they are found in the cells of all plants, animals, and humans. Microtubules can become up to several micrometer long, which is roughly the thickness of an average human hair.

The tubular structure of microtubules consists of a regular arrangement of two building blocks, the so-called tubulins (α-tubulin and β-tubulin). In a healthy cell, new microtubules are constantly formed from these building blocks - and are destroyed again. This process is regulated by numerous mechanisms, one of which is the so-called tubulin-tyrosine cycle. The amino acid tyrosine is either attached to the α-tubulin or cut off from it.

The enzymes that attach tyrosine to α-tubulin have been known for a long time. Without these enzymes nerve cells cannot connect properly in the brain. The enzymes that remove tyrosine from α-tubulin, the so-called vasohibins, have not been identified until 2017.

Studying molecular scissors at work

Cutting off the amino acid tyrosine from α-tubulin usually stabilises microtubules. Without tyrosine microtubules can remain intact for several hours, whereas the ones with tyrosine are usually broken down after a few minutes.

Researchers at the Paul Scherrer Institute PSI in Villigen have now succeeded for the first time in elucidating the exact structure of two vasohibins and studying how these enzymes remove the amino acid tyrosine from α-tubulin.

For this purpose, the vasohibins form a groove in their molecular structure that fits perfectly to the tyrosine-bearing end of α-tubulin. In order for this active centre to fit exactly to its target structure, the enzyme also needs an activator, the so-called "small vasohibin binding protein". This protein was previously only known as a stabiliser of vasohibins, but not as a stimulator of an enzymatic reaction. Precise structural analyses of the enzymatically active centre also show how inhibitors should look in order to inhibit vasohibins.

Another surprising result that the researchers achieved with their work: If the activity of the vasohibins is suppressed, disturbances occur in the development of nerve cells and their connections that are similar to those seen in the absence of their counterpart, the enzyme that attaches the amino acid tyrosine to α-tubulin. "A delicate balance between microtubules with and without tyrosine is the key for the normal formation of neurons", said Michel Steinmetz, head of the Laboratory for Biomolecular Research at PSI. "Our results clarify the structural basis of tubulin-detyrosination and clarify the relevance of this process for neuron development."

A possible route to new therapies

Since microtubules are involved in numerous other vital processes in the body in addition to the correct development of neuronal tissues, research on their formation and structure opens up new opportunities for medicine. For example, microtubules play an important role in the growth of tumours and the maintenance of healthy neurons. "With our structural elucidation of vasohibins in complex with inhibitors, we might now be able to develop novel types of drugs against diseases associated with unusual tubulin tyrosination, such as some cancers or possibly brain disorders", said Steinmetz.

With the structural elucidation of the vasohibins, it was possible for the first time to describe the complete tubulin-tyrosine cycle in detail. "This gives us completely new possibilities to intervene in this cycle with therapeutics and to develop new active substances for it", says Sung Ryul Choi, a biochemist at PSI and one of the first authors of the study.

To elucidate the structure of the vasohibins, the researchers used the Swiss Light Source SLS. "We were able to complete our structural work in about five months", said Choi. "This was only possible because here at PSI we have all the necessary expertise and infrastructure in one place."
The researchers have now published their results in the journal Nature Structural & Molecular Biology.

Text: Paul Scherrer Institute/Sebastian Jutzi

Images are available to download at

About PSI

The Paul Scherrer Institute PSI develops, builds and operates large, complex research facilities and makes them available to the national and international research community. The institute's own key research priorities are in the fields of matter and materials, energy and environment and human health. PSI is committed to the training of future generations. Therefore about one quarter of our staff are post-docs, post-graduates or apprentices. Altogether PSI employs 2100 people, thus being the largest research institute in Switzerland. The annual budget amounts to approximately CHF 407 million. PSI is part of the ETH Domain, with the other members being the two Swiss Federal Institutes of Technology, ETH Zurich and EPFL Lausanne, as well as Eawag (Swiss Federal Institute of Aquatic Science and Technology), Empa (Swiss Federal Laboratories for Materials Science and Technology) and WSL (Swiss Federal Institute for Forest, Snow and Landscape Research).


Dr. Michel Steinmetz
Laboratory of Biomolecular Research
Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland
Telephone: +41 56 310 47 54 , e-mail: [German, English]


Structural basis of tubulin detyrosination by the vasohibin-SVBP enzyme complex Na Wang, Christophe Bosc, Sung Ryul Choi, Benoit Boulan, Leticia Peris, Natacha Olieric, Hongyu Bao, Fatma Krichen, Liu Chen, Annie Andrieux, Vincent Olieric, Marie-Jo Moutin, Michel O. Steinmetz, Hongda Huang Nature Structural & Molecular Biology, 24 June 2019 DOI: 10.1038/s41594-019-0241-y

Paul Scherrer Institute

Related Nerve Cells Articles:

How hearing loss can change the way nerve cells are wired
Even short-term blockages in hearing can lead to remarkable changes in the auditory system, altering the behavior and structure of nerve cells that relay information from the ear to the brain, according to a new University at Buffalo study.
Lab-grown nerve cells make heart cells throb
Researchers at Johns Hopkins report that a type of lab-grown human nerve cells can partner with heart muscle cells to stimulate contractions.
Nerve-insulating cells more diverse than previously thought
Oligodendrocytes, a type of brain cell that plays a crucial role in diseases such as multiple sclerosis, are more diverse than have previously been thought, according to a new study by researchers at Karolinska Institutet in Sweden.
Aggregated protein in nerve cells can cause ALS
Persons with the serious disorder ALS, can have a genetic mutation that causes the protein SOD1 to aggregate in motor neurons in the brain and spinal cord.
Aggression causes new nerve cells to be generated in the brain
A group of neurobiologists from Russia and the USA, including Dmitry Smagin, Tatyana Michurina, and Grigori Enikolopov from Moscow Institute of Physics and Technology, have proven experimentally that aggression has an influence on the production of new nerve cells in the brain.
More Nerve Cells News and Nerve Cells Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Teaching For Better Humans
More than test scores or good grades — what do kids need to prepare them for the future? This hour, guest host Manoush Zomorodi and TED speakers explore how to help children grow into better humans, in and out of the classroom. Guests include educators Olympia Della Flora and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#535 Superior
Apologies for the delay getting this week's episode out! A technical glitch slowed us down, but all is once again well. This week, we look at the often troubling intertwining of science and race: its long history, its ability to persist even during periods of disrepute, and the current forms it takes as it resurfaces, leveraging the internet and nationalism to buoy itself. We speak with Angela Saini, independent journalist and author of the new book "Superior: The Return of Race Science", about where race science went and how it's coming back.