First 3D structure of the mini ‘cargo transporters’ inside our cells
Ever wondered how things get moved around inside a cell from one place to another? The answer lies in the form of mini ‘cargo transporters’ which travel along microscopic ‘railway tracks’ and now for the first time, scientists know what these transporters look like.
Dyneins are part of a family called motor proteins. They act as a ‘cargo transporters’ to move along ‘railway tracks’ called microtubules. Dyneins transport important cargo, including proteins and RNAs, to different parts of the cell and are crucial to ensure the cell can work properly.
For many years scientists have been trying to determine what these cargo transporters actually look like. Gradually, over time, the shape of various components of the dynein ‘cargo train’ have been revealed. Now work by Dr Andrew Carter’s group in the MRC Laboratory of Molecular Biology’s Structural Studies Division, in collaboration with Worldwide Cancer Research-funded scientist Dr Alexander Bird’s group at the Max Planck Institute Dortmund, has determined the 3D structure of the whole human dynein-1(called cytoplasmic dynein-1). They managed to visualise the shape of an inactive form and actually show how it is activated.
It is known that cytoplasmic dynein-1 sticks to dynactin, a group of proteins that switch dynein on. Dynein also sticks to cargo ‘adaptor proteins’ that couple the dynein/dynactin engine to cargo “carriages” capable of moving long distances along the microtubule ‘train tracks’.
Until now however, it was unclear why dynein-1 moves poorly on its own or how it is switched on or off. Using a combination of techniques, including cryo-electron microscopy, where the sample is studied using an electron microscope at cryogenic temperatures of -150 to -200 degrees C, the group have determined the shape and structure of complete human dynein-1 complex, in its inactive form, in extremely high detail.
The structure shows how the two ‘motor regions’ in dynein-1, responsible for the movement like the motor/engine in a speedboat or a train, stick together. This prevents the individual motors from being free to move and explains how they switch off their own activity. This can be seen in image 1. On the far left hand side, dark purple shape in the diagram below.
Disrupting these motor regions, by introducing mutations, prevents them from sticking to each other and forces dynein-1 into an open shape, as you can see in the second image.
The scientists found that the mutated, open form can stick to the microtubule railway tracks and dynactin, but is unable to move. The dynactin switch proteins relieve this by reorienting the motor regions to attach correctly on to the microtubule railway tracks. This explains how dynactin sticking to the dynein-1 tail directly encourages its motor activity.
The team also showed that stopping two dyneins from sticking together actually changes dynein’s location within cells and leads to defects in the way chromosomes line up and are segregated when cells divide, similar to defects that commonly occur in cancer cells. A number of mutations have also been found in the dynein motor regions that cause problems in cortical (brain) development, which can lead to developmental delay or epilepsy and many other diseases.
Now that scientists understand better what these dynein cargo transporters look like and how their motor engines are turned on and off, this knowledge may ultimately lead to new avenues for specifically controlling dynein activity in cells that might one day be used to treat diseases, including cancer, in patients.
The work was funded by Worldwide Cancer Research, the MRC and a Wellcome Trust New Investigator Award, and this text is adapted from an article by the MRC.
Image courtesy of the Medical Research Council (MRC).
Full reference: K. Zhang et al. Cryo-EM reveals how human cytoplasmic dynein is auto-inhibited and activated, Cell (2017). http://dx.doi.org/10.1016/j.cell.2017.05.025