Inscuteable: No longer inscrutable

The structure and function of a controller of stem cell division

An important complex forming the core of the cell division apparatus in stem cells has been imaged using the Macromolecular Crystallography beamlines, I04 and I04-1 at Diamond Light Source. As recently reported in Nature Communications, the spindle orientation protein known as LGN bound to an adapter protein known as Inscuteable in a tetrameric arrangement, which drove asymmetric stem cell division.

Stem cells are undifferentiated cells that have the capacity to differentiate into specialised cells. In a developing embryo, stem cells are the foundation of all other cells, whereas in adults, they can aid repair by replenishing lost tissue. To ensure a physiological balance between differentiated and undifferentiated cells, stem cells undergo asymmetric division to give rise to an identical daughter stem cell and a differentiated cell.

Asymmetric division occurs when there is an unequal segregation of cellular contents. For this to occur, the line of division of the cell (known as the axis) must be carefully positioned. The stem cells use polarity proteins, such as Par3, to determine the location of this axis, and then proteins such as LGN and Inscuteable (Insc) help to align the mitotic spindle to the axis of polarity.

Despite the importance of such a process, little is known about the interactions between the proteins. Dr Marina Mapelli, Group Leader at the European Institute of Oncology in Milan and Dr Simone Culurgioni, Post-Doctoral Research Associate here at Diamond, along with scientists from the Italian Institute of Technology, plus the European Molecular Biology Laboratory in Grenoble set out to solve the crystal structure of LGN bound to Insc. They saw that the proteins were intertwined in a fascinating tetrameric arrangement and found that Insc alone had impressive anti-proliferative properties.

>Read more on the Diamond Light Source website

Figure : On the left, a stem cell orienting (movement highlighted by the red arrow) its mitotic spindle (in green) in order to partition its cellular components (in pink and yellow) unequally in the two daughter cells; one is retaining the stem state (in pink) and the other one is committed to differentiate (in yellow). On the right, the structure of Insc:LGN complex governing this asymmetric cell division process. Insc:LGN complex assembles in highly stable intertwinned tetrameric structure (Insc in blue and purple, LGN in yellow and orange respectively
Entire image here.