Illustration: Tubulin being manipulated by metaphorical tweezers. Credit: Beat Fierz (EPFL)
A groundbreaking discovery in tubulin research has been made by a collaborative team of researchers from EPFL and the University of Geneva. They have successfully engineered “designer tubulins” with specific post-translational modifications (PTMs), shedding light on the intricate functions of tubulin. In particular, the investigation revealed a significant interaction between two crucial PTMs: polyglutamylation and detyrosination, which play essential roles in various diseases. To further explore these PTMs in immune cells, the team has been granted a Sinergia grant.
Tubulin, a vital protein, plays a fundamental role in cellular structure and function. It acts as the primary component of microtubules, long and hollow fibers that provide structural support, aid in cell division, maintain cell shape, and serve as pathways for intracellular transportation.
Two distinct types of tubulin exist: alpha-tubulin and beta-tubulin. Together, they form dimeric building blocks, spontaneously assembling into microtubules that undergo continuous cycles of assembly and disassembly.
The intricate tubulin code involves various post-translational modifications (PTMs) that fine-tune microtubules. These chemical modifications occur after tubulin synthesis and can impact their structure, activity, and interactions with other molecules. Notably, two significant PTMs occur on the unstructured tail of alpha-tubulin: polyglutamylation, involving the addition of chains of glutamate amino acids, and detyrosination, which removes the terminal tyrosine amino acid. Stable microtubules, such as those found in neurons, feature a combination of PTMs, including polyglutamylation and detyrosination.
Collectively, these PTMs contribute to what scientists refer to as the “tubulin code,” which is intricately linked to specific microtubule functions. Proper functioning of microtubules relies on the presence and regulation of tubulin PTMs.
Dysregulation of PTMs has been implicated in various diseases, including cancer, neurodegeneration, and developmental disorders. Therefore, understanding the significance of tubulin PTMs is crucial for advancing our knowledge of these diseases and developing potential therapeutic interventions. However, deciphering the mechanisms governing PTM patterns has been challenging due to limited tools available to analyze the function and regulation of tubulin PTMs.
To overcome this obstacle, scientists from EPFL and the University of Geneva have developed a chemical method to engineer fully functional tubulin with precise combinations of post-translational modifications (PTMs). This groundbreaking study, led by Professors Beat Fierz (EPFL) and Assistant-Professor Charlotte Aumeier (UNIGE), in collaboration with the labs of Pierre Gönczy (EPFL) and Carsten Janke (Institute Curie), provides valuable insights into how specific PTMs regulate tubulin function within cells.
The method employs chemo-enzymatic protein splicing to attach synthetic alpha-tubulin tails, modified with varying degrees of polyglutamate, to human tubulin molecules. By utilizing these “designer tubulins,” the researchers successfully assembled microtubules that were uniformly modified, a first in the field.
Furthermore, the research team discovered that polyglutamylation of alpha-tubulin enhances the activity of the protein complex vasohibin/SVBP, the key enzyme responsible for detyrosination. This finding was corroborated by manipulating polyglutamate levels in living cells and observing the subsequent effects on tyrosine removal.
This study introduces a novel approach to designing tubulins with specific PTMs and uncovers a new interplay between two key regulatory systems controlling tubulin function: polyglutamylation and detyrosination.
The newly developed method of generating tubulins with defined PTMs holds immense potential in advancing our understanding of their molecular function. Moreover, it provides valuable insights into how dysregulation of these PTMs contributes to various diseases.
Based on this groundbreaking work, the labs of Fierz and Aumeier, in collaboration with Jens Stein at the University of Fribourg and Michael Sixt at ISTA Vienna, have been awarded a Sinergia grant from the Swiss National Science Foundation. This grant aims to explore how tubulin PTMs control the cytoskeleton in migrating immune cells.
Reference: “Tubulin engineering by semisynthesis reveals that polyglutamylation directs detyrosination” by Eduard Ebberink, Simon Fernandes, Georgios Hatzopoulos, Ninad Agashe, Nora Guidotti, Timothy M. Reichart, Luc Reymond, Marie-Claire Velluz, Fabian Schneider, Cédric Pourroy, Carsten Janke, Pierre Gönczy, Beat Fierz, Charlotte Aumeier, 29 June 2023, Nature Chemistry.
DOI: 10.1038/s41557-023-01228-8
Other contributors:
- EPFL Swiss Institute for Experimental Cancer Research (ISREC)
- EPFL Biomolecular Screening Facility
- Université Paris Sciences & Lettres
- Université Paris-Saclay
Table of Contents
Frequently Asked Questions (FAQs) about tubulin code
What is the significance of tubulin in cellular mechanics?
Tubulin plays a crucial role in cellular mechanics as it is the main component of microtubules, which provide structural support, aid in cell division, maintain cell shape, and act as pathways for molecular transportation within cells.
What are post-translational modifications (PTMs) of tubulin?
Post-translational modifications (PTMs) are chemical modifications that occur on tubulin after it is synthesized. In the case of tubulin, two important PTMs are polyglutamylation, which adds chains of glutamate amino acids, and detyrosination, which removes the final tyrosine amino acid. These PTMs, along with others, form the “tubulin code” and are critical for the proper functioning of microtubules.
How do PTMs of tubulin relate to diseases?
Dysregulation of tubulin PTMs has been linked to various diseases, including cancer, neurodegeneration, and developmental disorders. Understanding the importance of these PTMs is crucial for advancing our knowledge of these diseases and developing potential therapies.
What are “designer tubulins” and how do they help in understanding the tubulin code?
“Designer tubulins” are tubulin molecules engineered with specific combinations of post-translational modifications (PTMs). By creating these modified tubulins, researchers can study how different PTMs affect the structure, function, and interactions of tubulin. This approach provides valuable insights into the complex tubulin code and its role in cellular mechanics.
How does the research contribute to understanding tubulin PTMs in immune cells?
The research has received a Sinergia grant to explore tubulin PTMs in immune cells. By investigating how PTMs control the cytoskeleton in migrating immune cells, researchers aim to gain a deeper understanding of the molecular mechanisms underlying immune cell function and potential implications for diseases related to tubulin dysregulation.
4 comments
The studie is super cool! They made desginer tublins! And it helpt to see how the PTMs work together. Diseases are affected too. Sooo cool!
wow, this is amazin! Scientists made designer tublins wit modifications, they craked the code! It helps understand diseases! #sciencerox
Tublin and microtubules are sooo interesting! They give cells structure and help with division. Now they discovered designer tublins to unlock their secrets. Nature is awesome!
Tublins are impotant in cells and they do PTMs. Those add and remove amino acids. This helps cells workin’ right. Diseaze connection cool!