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
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
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.'
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 &
Anastassis (Tassos) PerrakisGroup leader
PhD student utilizes evolution - Thesis Bart
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
Improving protein structure with homology-based
information and prior knowledge
Emile Voest, Anastassis Perrakis en Jannie Borst join
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 &
Borst investigates, among other things, how cytotoxic
T-cells fight tumors.
Anastassis Perrakis appointed Professor of
Macromolecular Structures at Utrecht University
(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
Anastassis (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
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
the development of novel drugs and safe and sustainable food
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
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
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 . Recently, they also launched the PDB_REDO
web-server that allows crystallographers to optimize their
structure models before deposition to the PDB .
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.
 See http://www.cmbi.ru.nl/pdb_redo and
 See http://xtal.nki.nl/PDB_REDO
Robbie 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.
Neil AaronsonGroup leader, ProfessorPDB_REDO web server
Back to group page