28 May 2019

Protein complex in cell nucleus developed from primal proteins

System that controls cell division resembles a mosaic

The protein complex that the cells of animals, plants, and fungi use to control cell division was created long ago from at least 40 different proteins. This could explain the overwhelming success of all cells with a cell nucleus, according to researchers at Utrecht University and the Hubrecht Institute. Their results were published in the scientific journal PNAS on 24 May.

“You might think that a fungus more closely resembles bacteria than it does us”, says Geert Kops, cell biologist at the Hubrecht Institute. “But that’s not the case. In contrast to the prokaryotic bacterial cells, the eukaryotic cells of fungi, plants, and animals all have a nucleus that stores the DNA.”

Cell division in cells with a nucleus: microtubules (red) are pulling the chromosomes (blue) towards both sides of the nucleus. On every chromosome, a kinetochore (light dots) is present. Image: Banafseh Etemad

Although both types of cells can replicate their DNA and then divide it among two new daughter cells, the systems by which prokaryotes and eukaryotes distribute the DNA among the daughter cells are completely different. Eukaryotes use what is known as a ‘kinetochore’; a protein complex that might have been crucial in their success.

Kinetochore gives starting shot for metaphase

Geert Kops is Professor of Molecular Tumour Cell Biology at the Hubrecht Institute, and a specialist in eukaryotic cell division. “The genetic material is recorded in the DNA in the chromosome. During cell division, both chromatids - the two copies of a chromosome - contain a protein complex that resembles a fairground grappling hook. This kinetochore ensures that all of the chromosomes form an orderly line in the middle of the nucleus. The cell only divides after all of the kinetochores have reported that they have completed their tasks. This is the start signal for the metaphase, in which the chromatids are pulled apart at the exact same time.”

UU Professor of Bioinformatics Berend Snel describes what this looks like when it occurs under a microscope. “At first, there’s one last chromosome that isn’t in position in the middle of the nucleus. And then, once that last chromosome has joined the rest, all of a sudden all of the chromatids let go and move to their own half.”


No intermediate form, and therefore indispensable

The kinetochore in every eukaryotic cell on Earth has a complex structure, while prokaryotic cells don’t have a kinetochore. In evolutionary theory, the absence of simple intermediate forms is an indication of the protein’s importance. Berend Snel, theoretical biologist at Utrecht University (UU): “That makes it even more relevant for us to find out how the protein complex developed. All of the kinetochores on Earth today should come from the same ancestor.”

The composition of the kinetochore in the last common ancestor (LECA) of all current eukaryotic cells exhibits the diverse origin of the protein. Clink on the image for a large view.

Data mining

Former PhD candidates Eelco Tromer (Hubrecht Institute) and Jolien van Hooff (UU) were able to unravel its lineage by combining an improved, more sensitive method for searching for comparable DNA sequences - and therefore relationships - with new insights into the composition of the protein complex.

Berend Snel: “We used 3D structures of the kinetochore’s sub-complexes that had been published by other scientists. By data mining through that information, we were able to determine how the system evolved. The protein complex appears to be a mosaic of at least 40 primordial proteins, which have been duplicated over and over again.”

Black hole of cell division

The publication provides insight into the development of life. Geert Kops, Hubrecht Institute: “An accurate, coordinated division is essential to a cell’s success. To me, the kinetochore is the black hole of eukaryotic cell division. We would very much like to know how the system developed, and how it functions in every organism on Earth. This work will contribute to that understanding.”


Mosaic origin of the eukaryotic kinetochore
Eelco Tromer*^, Jolien J.E. van Hooff*^, Geert J.P.L. Kops^ and Berend Snel*
PNAS, 24 May 2019
*  Affiliated to Utrecht University
^ Affiliated to the Hubrecht Institute and Oncode Institute


This research is conducted within the research domain Science for Life, part of Utrecht University’s interdisciplinary research theme Life Sciences.