Scientists explore structure underlying cell division in unprecedented detail

An international team of scientists used integrated structural biology techniques and live cell fluorescence microscopy to shed light on the architecture of budding yeasts’ inner kinetochore, a structure that plays a key role in cell division. Their findings were published online in The EMBO Journal.

During cell division in organisms with defined organelles and a nucleus, cells segregate their chromosomes, DNA molecules that their genome is packaged in, into daughter cells. The process of segregation is very regulated in space and time. It normally occurs with high fidelity.

Errors in the segregation process can lead to chromosome mis-segregation and the wrong number of chromosomes in the daughter cells. This is called aneuploidy and is a hallmark of human cancer cells, as well as a cause of human genetic disorders, such as Down Syndrome. Understanding the principles of chromosome segregation is therefore important, not last for medical applications.

An essential element of the segregation machinery is the kinetochore. Kinetochores connect microtubules - molecular ropes - with chromosomes. After kinetochores at all chromosomes attach to microtubules, the inactivation of the mitotic checkpoint, a gatekeeper, signals the cell to progress in its division. The study, which was published online in The EMBO Journal, shows the structural features of kinetochores in unprecedented resolution.

To achieve this, the scientists around Florian Schmitzberger, first at Harvard Medical School and the Research Institute of Molecular Pathology (IMP), and Stefan Westermann, a former group leader at the IMP; both now at the University of Duisburg-Essen, analysed a set of six proteins from budding yeasts’ inner kinetochore that form an assembly. They recreated this assembly in the test tube, and analysed its arrangement and molecular structure.

In collaboration with Carol Robinson and Yuliya Gordiyenko of the University of Oxford, and Micha? Dadlez and Magdalena Richter of the Polish Academy of Sciences, they used mass spectrometry, to analyse the assembly in its folded state and to determine flexible parts and parts that bind to other proteins. In doing so, they created a map of how these six proteins arrange and connect with each other. They also determined the high-resolution 3D structure of three kinetochore proteins with crystallography.

Their study provides insight into inner kinetochore architecture: flexible proteins are molecular nexuses that connect with globular parts, so-called RWD domains, of other kinetochore proteins.

The protein composition of budding yeasts’ kinetochores is very similar to that of the human kinetochore. Studying the structure and function of the kinetochore from budding yeasts, as described in their study, will help to understand kinetochore function in general, including that in humans.

Original publication

Schmitzberger, F. et al.: “Molecular basis for inner kinetochore configuration through RWD domain–peptide interactions”.
http://emboj.embopress.org/cgi/doi/10.15252/embj.201796636

About the IMP

The Research Institute of Molecular Pathology (IMP) in Vienna is a basic biomedical research institute largely sponsored by Boehringer Ingelheim. With over 200 scientists from nearly 40 nations, the IMP is committed to scientific discovery of fundamental molecular and cellular mechanisms underlying complex biological phenomena. Research at the IMP addresses topics in molecular and cellular biology; structural biology and biochemistry; gene expression and chromosome biology; stem cell biology and development; immunology and cancer; and neuroscience. The IMP is located at the Vienna BioCenter.

About the Vienna BioCenter

Vienna BioCenter (VBC) is a leading life sciences hub in Europe, offering an extraordinary combination of research, business and education in a single location. About 1,700 employees, 86 research groups, 18 biotech companies, 1,300 students, and scientists from 69 nations create a highly dynamic and stimulating environment. http://www.viennabiocenter.org