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Swinging on 'monkey bars': Motor proteins caught in the act

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  • Ref Swinging on 'monkey bars': Motor proteins caught in the act

    An understanding of motor proteins is important to medical research because of their fundamental role in complex cellular life. Many viruses hijack motor proteins to hitch a ride to the nucleus for replication. Cell division is driven by motor proteins and so insights into their mechanics could be relevant to cancer research. Some motor neuron diseases are also associated with disruption of motor protein traffic.

    The team at Leeds, working within the world-leading Astbury Centre for Structural Molecular Biology, combined purified microtubules with purified dynein motors and added the chemical fuel ATP (adenosine triphosphate) to power the motor.

    Dr Hiroshi Imai, now Assistant Professor in the Department of Biological Sciences at Chuo University, Japan, carried out the experiments while working at the University of Leeds.

    He explained: "We set the dyneins running along their tracks and then we froze them in 'mid-stride' by cooling them at about a million degrees a second, fast enough to prevent the water from forming ice crystals as it solidified. Then using a cryo-electron microscope we took many thousands of images of the motors caught during the act of stepping. By combining many images of individual motors, we were able to sharpen up our picture of the dynein and build up a dynamic idea of how it moved. It is a bit like figuring out how to swing along monkey bars by studying photographs of many people swinging on them."

    Dr Burgess said: "Our most striking discovery was the existence of a hinge between the long, thin stalk and the 'grappling hook', like the wrist between a human arm and hand. This allows a lot of variation in the angle of attachment of the motor to its track.

    "Each of the two arms of a dynein motor protein is about 25 nanometres (0.000025 millimetre) long, while the binding sites it attaches to are only 8 nanometres apart. That means dynein can reach not only the next rung but the one after that and the one after that and appears to give it flexibility in how it moves along the 'track'."

    Dynein is not only the biggest but also the most versatile of the motor proteins in living cells and, like all motor proteins, is vital to life. Motor proteins transport cargoes and hold many cellular components in position within the cell. For instance, dynein is responsible for carrying messages from the tips of active nerve cells back to the nucleus and these messages keep the nerve cells alive.

    Co-author Peter Knight, Professor of Molecular Contractility in the University of Leeds' School of Molecular and Cellular Biology, said: "If a cell is like a city, these are like the truckers on its road and rail networks. If you didn't have a transport system, you couldn't have specialised regions. Every part of the cell would be doing the same thing and that would mean you could not have complex life."

    "Dynein is the multi-purpose vehicle of cellular transport. Other motor proteins, called kinesins and myosins, are much smaller and have specific functions, but dynein can turn its hand to a lot of different of functions," Professor Knight said.

    For instance, in the motor neuron connecting the central nervous system to the big toe--which is a single cell a metre long-- dynein provides the transport from the toe back to the nucleus. Another vital role is in the movement of cells.

    Dr Burgess said: "During brain development, neurons must crawl into their correct position and dynein molecules in this instance grab hold of the nucleus and pull it along with the moving mass of the cell. If they didn't, the nucleus would be left behind and the cytoplasm would crawl away."

    Direct observation shows superposition and large scale flexibility within cytoplasmic dynein motors moving along microtubules

    Cytoplasmic dynein is a dimeric AAA+ motor protein that performs critical roles in eukaryotic cells by moving along microtubules using ATP. Here using cryo-electron microscopy we directly observe the structure of Dictyostelium discoideum dynein dimers on microtubules at near-physiological ATP concentrations. They display remarkable flexibility at a hinge close to the microtubule binding domain (the stalkhead) producing a wide range of head positions. About half the molecules have the two heads separated from one another, with both leading and trailing motors attached to the microtubule. The other half have the two heads and stalks closely superposed in a front-to-back arrangement of the AAA+ rings, suggesting specific contact between the heads. All stalks point towards the microtubule minus end. Mean stalk angles depend on the separation between their stalkheads, which allows estimation of inter-head tension. These findings provide a structural framework for understanding dynein’s directionality and unusual stepping behaviour.

    Study Overturns Seminal Research About the Developing Nervous System


    As an embryo grows, neurons — the cells in the nervous system — extend axons into the developing spinal cord. Axons are then guided to reach other areas of the body, such as the brain, to establish a functioning nervous system. It has been generally understood that various guidance cues, which are cellular molecules such as proteins, either attract or repel axon growth as the axons reach out from neurons to find their destination in the nervous system.

    Previous research suggested that a particular guidance cue, called netrin1, functions over a long distance to attract and organize axon growth, similar to how a lighthouse sends out a signal to orient a ship from afar. However, previous research also shows that netrin1 is produced in many places in the embryonic spinal cord, raising questions about whether it really acts over a long distance. Most notably, netrin1 is produced by tissue-specific stem cells, called neural progenitors, which can create any cell type in the nervous system. Yet, it was not understood how the netrin1 produced by neural progenitors influences axon growth.


    Butler and her research team removed netrin1 from neural progenitors in different areas in mouse embryonic spinal cords. This manipulation resulted in highly disorganized and abnormal axon growth, giving the researchers a very detailed view of how netrin1 produced by neural progenitors influences axons in the developing nervous system.

    They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.


    Butler’s study is a significant reinterpretation of the role of netrin1 in nervous system formation. The results further scientists’ understanding of the contribution neural progenitors make to neural circuit formation. Determining how netrin1 specifically influences axon growth could help scientists use netrin1 to regenerate axons more effectively in patients whose nerves have been damaged.

    For example, because nerves grow in channels, there is much interest in trying to restore nerve channels after an injury that results in severed nerves, which is seen often in patients who have experienced an accident or in veterans with injuries to their arms or legs. One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Butler believes that coating such nerve channels with netrin1 could further encourage axon regrowth. Her continued research will focus on uncovering more details about how netrin1 functions and how it could be used clinically.
    Update 20/04/2017
    Last edited by Jo Bowyer; 21-04-2017, 12:06 AM.
    Jo Bowyer
    Chartered Physiotherapist Registered Osteopath.
    "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi

  • #2
    Isn't it amazing we can see these tiny motors and they are about 20 nanometer


    "Evolution is a tinkerer not an engineer" F.Jacob
    "Without imperfection neither you nor I would exist" Stephen Hawking


    • #3
      I think so,

      I like the idea of the cell as a city.
      Jo Bowyer
      Chartered Physiotherapist Registered Osteopath.
      "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi


      • #4
        Cortical dynein pulling mechanism is regulated by differentially targeted attachment molecule Num1

        Proper positioning of the mitotic spindle is essential for successful cell division and is crucial for a wide range of processes including creation of cellular diversity during development, maintenance of adult tissue homeostasis, and balancing self-renewal and differentiation in progenitor stem cells (Galli and van den Heuvel, 2008; Gómez-López et al., 2014; Morin and Bellaïche, 2011; Siller and Doe, 2009). In various cell types, spindle positioning involves attachment of the minus end-directed MT motor cytoplasmic dynein to the cell cortex, where it exerts pulling force on astral MTs that emanate from the spindle poles (di Pietro et al., 2016; Kotak and Gönczy, 2013; McNally, 2013). While proteins involved in anchoring dynein have been identified (Ananthanarayanan, 2016; Couwenbergs et al., 2007; Du and Macara, 2004; Heil-Chapdelaine et al., 2000; Kotak et al., 2012; Nguyen-Ngoc et al., 2007; Saito et al., 2006; Thankachan et al., 2017) and the mechanism whereby dynein steps along the MT is becoming elucidated (DeSantis et al., 2017; DeWitt et al., 2015; Grotjahn et al., 2018; Nicholas et al., 2015; Urnavicius et al., 2018), how pulling forces are precisely regulated to achieve the appropriate spindle displacement remains incompletely understood.
        Jo Bowyer
        Chartered Physiotherapist Registered Osteopath.
        "Out beyond ideas of wrongdoing and rightdoing,there is a field. I'll meet you there." Rumi