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Precise interplay between STIL and PLK4 guarantees flawless cell division

When cells divide, they not only duplicate their genetic material, but also small cell organelles known as centrioles. Both processes must proceed error-free in order to prevent tumor formation. The closely coordinated interplay of two proteins – STIL and PLK4 – plays a decisive role in centriole duplication. In their recently published study in "eLife", researchers at the Biozentrum, University of Basel, provide new insights into the structure and mode of function of these two proteins and thus elucidate one of the first steps in the formation of centrioles.

Overexpression of STIL (green) leads to the formation of too many daughter centrioles (Blue: PLK4).

The division of cells and their genetic information is a tricky matter. Even the smallest mistake can have massive consequences, including cell death or tumor formation. A decisive role in the segregation of chromosomes is exerted by the centrioles. Prior to cell division they are duplicated and then divided between the two daughter cells. The research groups led by Prof. Timm Maier, Prof. Sebastian Hiller and Prof. Erich Nigg, all at the Biozentrum of the University of Basel, have now demonstrated that the proteins STIL and PLK4 jointly control centriole duplication.

The proteins STIL and PLK4 jointly regulate centriole formation

Every animal cell contains exactly one pair of centrioles. They are the core component of the centrosomes, the major organizing centers for the spindle apparatus. It is the spindle apparatus that segregates and evenly distributes the chromosomes. This is important to ensure that the two daughter cells each contain a complete set of chromosomes after cell division. Errors in centriole duplication may cause the formation of too many or too few centrosomes. And, importantly, extra centrosomes and a resulting abnormal number of chromosomes frequently occur in cancer cells.

Using X-ray crystallography and nuclear magnetic resonance spectroscopy, the researchers were able to examine the interplay between the two proteins, STIL and PLK4, based on the three-dimensional structures of the interacting fragments. "We have now been able to show how precisely a helical part of the protein STIL, the so-called coiled-coil domain, interacts with PLK4", explains Christian Arquint, a postdoc in Erich Nigg’s lab. "With the help of the structural data, we gained new insights into the way both of these proteins function."

STIL and PLK4 are interdependent

Based on these findings, STIL and PLK4 strictly depend on each other during centriole duplication. When STIL levels are reduced, the enzyme PLK4 is bound to the mother centriole and appears to be inactive. The binding of STIL to PLK4 then results in PLK4 activation, so that the enzyme can unfold its full action. Firstly, PLK4 modifies its partner STIL and thus initiates the formation of the daughter centrioles. Furthermore, all neighboring STIL-free PLK4 enzymes are biochemically altered and degraded. "We assume that STIL maintains appropriate levels of active PLK4 at the centrioles", says Arquint.

Focus on the formation of new daughter centrioles

For the duplication of centrioles the cell requires a number of proteins. These are evolutionarily conserved from the fruit fly to humans. An excess of these proteins, including STIL and PLK4, in the cell can result in the formation of extra centrioles. In contrast, an insufficient amount leads to the inhibition of this process. Therefore, the two proteins are key factors for correct centriole duplication and their activity and expression must be strictly controlled. Further experiments now aim to address the question of how the initial position of daughter centriole growth is determined in time and space.

Original article:
Christian Arquint, Anna-Maria Gabryjonczyk, Stefan Imseng, Raphael Böhm, Evelyn Sauer, Sebastian Hiller, Erich A Nigg, Timm Maier. STIL binding to Polo-box 3 of PLK4 regulates centriole duplication. eLife; published online 18 July 2015.

Contact: Communications; Katrin Bühler