Cellular chariots

TSRI researchers link cellular cargo transport machinery to neurological disorders

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LA JOLLA, Calif.—Motor proteins called dyneins “walk” along structures called microtubules to deliver cellular cargo, such as signaling molecules and organelles, to different parts of a cell. Without dynein, cells cannot divide and people can develop neurological diseases.
A new study, published in the journal Nature Structural & Molecular Biology, offers the first three-dimensional visualization of the dynein-dynactin complex bound to microtubules. The study was supported by the National Institutes of Health, the National Science Foundation, the Searle Scholars Program, the Pew Scholars Program and the Johns Hopkins Krieger School of Arts and Sciences.
Researchers from The Scripps Research Institute (TSRI) report that a protein called dynactin hitches two dyneins together, like a yoke locking together a pair of draft horses. According to Dr. Gabriel C. Lander, associate professor at The Scripps Research Institute (TSRI) and senior author of the study, “If you want a team of horses to move in one direction, you need to line them up. That’s exactly what dynactin is doing to dynein molecules.”
Understanding how the dynein-dynactin complex is assembled and organized provides a critical foundation to explain the underlying causes of several dynein-related neurodegenerative diseases such as spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) disease. Postdoctoral research associates Danielle Grotjahn and Saikat Chowdhury elaborated on the study.
Grotjahn and Chowdhury explained that neurons are specialized cells that transmit information throughout the brain and the central nervous system. They contain a unique cellular morphology/shape that includes the presence of highly elongated projections called axons. These axonal projections can be extremely long, up to a meter in length for some neurons. For a neuron to function properly, nutrients, signaling molecules and proteins need to be carried out or transported throughout these elongated axons, and the dynein-dynactin complex plays an essential role in this process. Dynein-dynactin complexes are microscopic, force-producing engines that can bind to these cellular components and transport them along the cell’s molecular “highway,” structures called microtubules. Without the proper delivery of these components, neurons cannot function properly and, eventually, inefficient transport can lead to cell death.
In addition to these components, the dynein-dynactin complex also transports damaged proteins or protein aggregates to the cell’s degradation machinery where they can be processed and eliminated. A hallmark feature of many neurodegenerative diseases is the uncontrollable buildup of these damaged proteins. The dynein-dynactin complex plays an important role in the transport of “good” cellular components and the clearance of “bad” disease-causing proteins, further emphasizing their important role for neuron cell health and viability.
“Defects to the dynein-dynactin transport machinery are associated with a large variety of neurological and neurodegenerative diseases such as SMA and CMT,” the researchers said. “Investigating the mechanisms by which the dynein-dynactin complex is assembled and organized in healthy neurons will build a vital foundation to understand how this complex may be disrupted in disease and may eventually lead to the development of therapeutics to ameliorate the progression of these devastating diseases.”
Prior studies had shown that dynein motors require the binding of two cofactors—dynactin and a cargo adaptor protein—to exhibit fast, efficient movement along microtubule “tracks” in cells. These prior studies used light microscopy, a very powerful experimental tool enabling the researcher to specifically label any component within a protein complex and then record a movie of its movement to analyze parameters such as speed and distance of travel. One of the limitations of this technique is that it does not contain high-resolution information regarding the structure of the labeled protein, meaning that it cannot visualize the fine, molecular details of cellular components such as the dynein-dynactin complex.
As the researchers explained, “One way to think about this is to imagine you’re flying in a helicopter, looking down over a highway. You can see the overall movement of the cars below, but you can’t really see any other details. If you wanted to fundamentally understand how movement of the cars is achieved, you need to zoom in to get a better look at the details of the car, such as the tires or the engine. That’s essentially what we did in this study to understand the dynein-dynactin complex. We used a specialized microscopy technique called cryo-electron tomography, which has the ability to view the fine details of protein structure, much more than light microscopy. By examining these fine details, much like examining the cars up-close, we can learn more about how this transport functions. Our study provides the first three-dimensional view of the dynein-dynactin complex, thereby giving us the first glimpse at how the entire complex is organized.”
Microscopy has played an important role not only in the discovery of dynein motors, but also for understanding the mechanisms by which these motors function in cells. The researchers had a pretty good idea of what dynein on its own looked like, thanks to previous electron microscopy studies, but they did not have a good grasp on what the entire dynein motor looked like when attached to dynactin.
“Thanks to technological advancements in the field, electron microscopy has undergone a rapid maturation and has become one of the leading techniques for high-resolution structure determination of biological proteins,” they said. “Taking advantage of these improvements to better capture and process electron microscopy images, we were able to visualize the dynein-dynactin complex in ways that have not been possible previously. Although other groups had elucidated high-resolution structures of individual parts or components of this complex, our structure is the first full, three-dimensional view. Therefore, instead of representing this complex as simple shapes and generalized cartoon schematics, cell biology and biochemistry textbooks can use our structure as a template to describe and represent this protein complex more accurately.
“Furthermore, our structure revealed a surprising discovery: the discovery of two dynein motors attached to dynactin. This was unexpected because it was previously assumed in the field that there was a single dynein motor bound to dynactin, and most cartoon or graphical representations of the dynein-dynactin complex reflected this by only having a single dynein. Therefore, not only does our structure provide a template to represent the complete 3D architecture of the dynein-dynactin complex, it also fundamentally changes the way it is represented.”
Previous studies using complementary experimental approaches demonstrated that dynein motors like to cluster together so that they can work collectively as a team to generate large forces to transport cellular cargo. Based on the TSRI discovery that dynactin recruits and bind to two dynein motors, this suggests that dynactin recruits a mini-team comprised of a pair of dynein motors. Therefore, TSRI’s structure suggests that by grouping two dyneins to a single scaffold, nature has found a way to create a micro-motor team that doubles the amount of force produced per dynactin scaffold, thereby maximizing the potential to cluster motors and thus potentially saving valuable “real estate” space around the surface of a particular cargo.

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