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Updates Biochemistry : Anastassis (Tassos) Perrakis group

Solving a Molecular Scissors Mystery

A Netherlands Cancer Institute team, co-led by Thijn Brummelkamp and Anastassis (Tassos) Perrakis, reported independently, but almost simultaneously with three more groups from all over the world, on the crystal structure and mechanism of a peculiar molecular end-tail of the microtubules that constitute the cell skeleton.

A cell skeleton is made of cables called microtubules. These allow a cell to maintain its shape, move to different places and transport molecules through its interior. Microtubules also play a key role in cell division.

The frequently used cancer therapeutic paclitaxel, aimed at cells that are dividing, specifically acts on microtubules and thereby affects their detyrosination. In addition, detyrosynation of tubulin has been implicated in cardiac dysfunction, correct segregation of chromosomes during mitosis, and mental retardation.

Microtubules are continuously modified to serve different purposes within the cell. For this, their tyrosine tails are cut and put back by different enzymes. After researchers from the Netherlands Cancer Institute and Oncode Institute, in 2017, found the identity of the scissors that remove the tail, an apparent race was launched to solve the next piece of the puzzle: to determine the 3D structure of these molecular scissors.

This month the Netherlands Cancer Institute team, co-led by Thijn Brummelkamp and Anastassis (Tassos) Perrakis, independently but almost simultaneously with three more groups from all over the world, are reporting on the crystal structure and mechanism of these peculiar molecular end-tail scissors. Tassos Perrakis: 'This means that a beautiful consensus is emerging, supported by complementary experiments which together have been constructing an exciting story.' 

More information: Solving a Molecular Scissors Mystery

Athanasios Adamopoulos et al., 'Crystal structure of the VASH1-SVBP complex, a 2 tubulin tyrosine carboxypeptidase', Nature Structural & Molecular Biology, 1 July 2019.

Kevin C. Slep. 'Cytoskeletal cryptography: structure and mechanism of an eraser', Nature Structural & Molecular Biology3 July 2019 (News & Views). 

Anastassis Perrakis.jpgAnastassis (Tassos) PerrakisGroup leader

PhD student utilizes evolution - Thesis Bart van Beusekom

Did you know that human DNA copy machines are almost identical to those of chimpanzees? Researcher Bart van Beusekom from the Netherlands Cancer Institute used such similarities to develop software that allows scientists to better solve new protein structures. On Monday May 27th he will defend his PhD thesis at Utrecht University.
 
Life is driven by proteins as molecular machines. To properly understand these, detailed 3D protein structure models are needed, giving unique insight into biology and helping the development of new drugs. Proteins are highly dependent on their 3D folding for properly performing their functions. However, obtaining reliable protein structure models is challenging and labor-intensive. That's why researcher Bart van Beusekom and colleagues of The Netherlands Cancer Institute developed software that optimizes thousands of protein structure models to make them more complete and reduce errors. Van Beusekom: "This allows us to better understand the biology and the automation also saves scientists' valuable time. Our software is used by over 10,000 people each month."

The methods they've created make frequent use of the concept of homology. Van Beusekom: "Homologous protein structures remain similar during evolution. For instance, the proteins that copy DNA are almost identical  in humans and chimpanzees, but even those from tomatoes have similar 3D structures. Existing data of solved homologous structures is oftentimes not used optimally when solving a new one. That's why we have developed a website showing scientists where and how a structure model is different from its homologs. Our methods are the first to systematically use all available homologous protein structure models to improve new models in several ways."

Want to know more? Download Bart van Beusekom's thesis here.     

Practical information about the defense can be found on Utrecht University's website.

Improving protein structure with homology-based information and prior knowledge

LAHMA Local Annotation of Homology Matched Amino acids

Emile Voest, Anastassis Perrakis en Jannie Borst join Oncode

Three group leaders and their research groups from the Netherlands Cancer Institute join Oncode Institute per 2019. A selection committee of (inter)national experts selected  19 researchers from 160 applicants. With over 800 cancer researchers the Oncode team is now complete.

Medical director, medical oncologist and scientist Emile Voest aims to answer questions such as: how are tumor cells recognized by the immune system? And how do they escape? Group leader Anastassis (Tassos) Perrakis of the Biochemistry division investigates macromolecular structures (large molecules), in order to eventually translate basic research into new therapies. Group leader and head of the division Tumor Biology & Immunology Jannie Borst investigates, among other things, how cytotoxic T-cells fight tumors.

Anastassis Perrakis appointed Professor of Macromolecular Structures at Utrecht University

Biochemist Anastassis (Tassos) Perrakis has been appointed Endowed Professor of Macromolecular Structures at Utrecht University. Perrakis is a researcher and group leader at the Netherlands Cancer Institute and an expert in unravelling cancer proteins.

Anastassis Perrakis studies the proteins that play a role in the development of cancer, but he also develops techniques for analysing their structures. In his field, he is mainly known for his contributions to macromolecular crystallography, the creation of large proteins.
 
The most important method for analysing proteins is X-ray diffraction, a technique that makes it possible to determine the positions of atoms in a protein with extreme accuracy. The various software tools that Perrakis has developed make the process faster and more effective.

Software for protein models

Together with his research group at the Netherlands Cancer Institute (NKI), in 1999 Perrakis developed the software ARP/wARP, which is now commonly used to show the structure of a protein. 'With this software, crystallographers can automatically create a structure model of a molecule based on their own X-ray experiments, whether they are new to the field or already have plenty of experience', according to Perrakis. 'In the past, they had to spend weeks, or even months, in front of expensive computer equipment.' The ARP/wARP software has a few thousand users and has been cited in scientific publications more than 5,000 times.

Read more on the website of Utrecht University

Anastassis Perrakis.jpgAnastassis (Tassos) PerrakisGroup leader

Veni grant for Yoshitaka Hiruma

Yoshitaka Hiruma, postdoc in the group of Anastassis Perrakis, will receive a Veni grant from the Netherlands Organisation for Scientific Research (Dutch abbreviation: NWO). He will use the grant of 250.000 Euro to further study the role of the Mps1 protein during cell division.

Errors during cell division can cause all kinds of problems, including cancer. The division process consists of a number of separate phases. Between these phases there exist several checkpoints, molecular mechanisms that the cell uses to check whether it is safe to progress to the next phase. One such checkpoint is between the metaphase and anaphase. During the metaphase, the chromosomes are lined up and connected to the spindle apparatus. It is very important that all chromosomes are properly connected to the spindle microtubules, so that they will be neatly pulled apart and divided over the two daughter cells. Recently, Hiruma was the first author of a Science paper in which he and his colleagues describe how cells use the Mps1 protein to check whether all chromosomes are properly connected.

The majority of solid tumors contain cells with an aberrant number of chromosomes, pointing to problems in the process described above. Hiruma now wants to study the Mps1 protein on the level of specific molecular and atomic interactions . Understanding the structures of the transient complexes that Mps1 makes during cell division,  could hopefully lead to the development of inhibitors of Mps1 interactions, that might in the future be developed as new anti-cancer drugs.

European Union invests 10 million Euro in research on the structure and function of complex proteins

Aim of this initiative called iNEXT, is to determine new structures and functions of proteins and their complexes, by giving researchers integrated access to structural biology technologies such as NMR, electron microscopy and X-ray technologies. The project contributes to European goals for health and green economy, as fundamental knowledge of biological processes is important, for example, for
the development of novel drugs and safe and sustainable food production methods.

                               Groundbreaking research

iNEXT will provide access to the most advanced facilities for structural biology in Europe. The collaborating facilities include advanced X-ray synchrotron sources in Grenoble, Hamburg, Oxford, Lund and Paris, high-field NMR facilities in Utrecht, Frankfurt, Florence, Brno, Lyon and Grenoble, imaging facilities in Oxford, Brno, Heidelberg, Leiden and Madrid and advanced biophysical characterization in Amsterdam. Together, these facilities will make it possible for European scientists to perform ground breaking protein research with technologies to which they otherwise would not have had access.

                               Starting September 2015

iNEXT (www.inext-eu.org) is coordinated from the Netherlands by prof. Rolf Boelens (Utrecht University) with dr. Anastassis Perrakis (Netherlands Cancer Institute) as deputy coordinator. The program is
setup in coordination with the European ESFRI projects Instruct, ESS, EU-OPENSCREEN and Euro-BioImaging. Researchers across Europe will be able to apply for access to the advanced facilities of iNEXT through a peer-review process. Starting September 1, 2015, the facilities will be available and
proposals for access can be submitted.

Vidi Grant for Robbie Joosten - juni 2014

NKI researcher dr. Robbie Joosten has received a Vidi grant from the Netherlands Organization for Scientific Research (NWO). With the grant money of 800.000 Euros, he can develop his own research line.

Joosten works on the 3D structure of proteins. Comprehensive knowledge of protein structure is essential for understanding molecular mechanisms of diseases. Within cancer research, high quality protein structures can be used to explain the effect of disease-causing mutations and provide structural scaffolds for drug design. Protein structures are determined experimentally, mostly through X-ray crystallography. And with great success: in May 2014 the 100,000th structure was made publicly available through the Protein Data Bank (PDB).

However, the quality of the protein structure models is limited by the quality of the available data, the tools used to make the models and the skill and experience of the scientists using these tools. Joosten focuses on improving the digital tools that are used to make the models. He and his colleagues developed the automated PDB_REDO framework. With this framework, it is possible to improve protein structure models using their original crystallographic data. PDB_REDO combines decision-making algorithms  with model building algorithms to deliver optimized structure models,  with improved fit to their X-ray data and to broader chemical knowledge. Joosten and his colleagues applied PDB_REDO to all published X-ray structures, yielding the publicly available PDB_REDO data bank of optimized, consistently treated structure models [1]. Recently, they also  launched the PDB_REDO web-server that allows crystallographers to optimize their structure models before deposition to the PDB [2].

With the Vidi grant Joosten will bring PDB_REDO to a new level of sophistication that provides evolutionary context to structures. This context is key to exploit  structural insight, because conserved features, clade-specific characteristics, and  deviations from "normality" hint towards specific biology and medical relevance. To do this he will develop algorithms to detect and thoroughly validate 'unusual' features of protein structures, such as localized multiple conformations, post-translational modifications, and ligand binding. He will then use these structural features to integrate structural knowledge from all homologous structures into individual structures. This allows for the detection of important structural details, even when the data is relatively poor, and will lead to higher quality, more informative protein structures for biomedical research.

[1] See http://www.cmbi.ru.nl/pdb_redo and its references.

[2] See http://xtal.nki.nl/PDB_REDO

Joosten, Robbie.jpgRobbie JoostenResearch associate

Vacancy for an enthusiastic Biochemist!

A vacancy to work together with the group of Prof. Dr. Geert Kops in the function and structure of the BubR1 pseudo-kinase and the Mps1 kinase is available for an enthusiastic biochemist

Ph.D. degree Jens Hausmann

Jens Hausmann defended his thesis on the structure and function of Autotaxin at Leiden University!

Link to thesis Jens Hausmann

Release of the PDB_REDO server
 
Robbie Joosten and Anastassis Perrakis have announced the PDB_REDO web server, to help crystallographer construct more accurate models of their structures.

NeilAaronson.jpgNeil AaronsonGroup leader, Professor

PDB_REDO web server

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