MSGID: 1:317/3 645486d3   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Alternative 'fuel' for string-shaped motors in cells    
      
     Date:   
         May 4, 2023   
     Source:   
         Technische Universita"t Dresden   
     Summary:   
         Researchers discover a unique two-component molecular motor that   
         uses a kind of renewable chemical energy to pull vesicles toward   
         membrane-bound organelles.   
      
      
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   FULL STORY   
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   Cells have a fascinating feature to neatly organize their interior   
   by using tiny protein machines called molecular motors that generate   
   directed movements.   
      
   Most of them use a common type of fuel, a kind of chemical energy, called   
   ATP to operate. Now researchers from the Max Planck Institute of Molecular   
   Cell Biology and Genetics (MPI-CBG), the Cluster of Excellence Physics   
   of Life (PoL) and the Biotechnology Center (BIOTEC) of the TU Dresden in   
   Dresden, Germany, and the National Centre for Biological Sciences (NCBS)   
   in Bangalore, India, discovered a novel molecular system that uses an   
   alternative chemical energy and employs a novel mechanism to perform   
   mechanical work. By repeatedly contracting and expanding, this molecular   
   motor functions similarly to a classical Stirling engine and helps to   
   distribute cargo to membrane-bound organelles. It is the first motor   
   using two components, two differently sized proteins, Rab5 and EEA1,   
   and is driven by GTP instead of ATP. The results are published in the   
   journal Nature Physics.   
      
   Motor proteins are remarkable molecular machines within a cell that   
   convert chemical energy, stored in a molecule called ATP, into mechanical   
   work. The most prominent example is myosin which helps our muscles to   
   move. In contrast, GTPases which are small proteins have not been viewed   
   as molecular force generators. One example is a molecular motor composed   
   of two proteins, EEA1 and Rab5. In 2016, an interdisciplinary team of   
   cell biologists and biophysicists in the groups of MPI-CBG directors   
   Marino Zerial and Stephan Grill and their colleagues, including PoL   
   and BIOTEC research group leader Marcus Jahnel, discovered that the   
   small GTPase protein Rab5 could trigger a contraction in EEA1. These   
   string-shaped tether proteins can recognize the Rab5 protein present   
   in a vesicle membrane and bind to it. The binding of the much smaller   
   Rab5 sends a message along the elongated structure of EEA1, thereby   
   increasing its flexibility, similar to how cooking softens spaghetti. Such   
   flexibility change produces a force that pulls the vesicle towards   
   the target membrane, where docking and fusion occur. However, the team   
   also hypothesized that EEA1 could switch between a flexible and a rigid   
   state, similar to a mechanical motor motion, simply by interacting with   
   Rab5 alone.   
      
   This is where the current research sets in, taking shape via the doctoral   
   work of the two first authors of the study. Joan Antoni Soler from Marino   
   Zerial's research group at MPI-CBG and Anupam Singh from the group of   
   Shashi Thutupalli, a biophysicist at the Simons Centre for the Study   
   of Living Machines at the NCBS in Bangalore, set out to experimentally   
   observe this motor in action.   
      
   With an experimental design to investigate the dynamics of the EEA1   
   protein in mind, Anupam Singh spent three months at the MPI-CBG in   
   2019. "When I met Joan, I explained to him the idea of measuring   
   the protein dynamics of EEA1. But these experiments required specific   
   modifications to the protein that allowed measurement of its flexibility   
   based on its structural changes," says Anupam.   
      
   Joan Antoni Soler's expertise in protein biochemistry was a perfect fit   
   for this challenging task. "I was delighted to learn that the approach   
   to characterize the EEA1 protein could answer whether EEA1 and Rab5   
   form a two- component motor, as previously suspected. I realized that   
   the difficulties in obtaining the correct molecules could be solved by   
   modifying the EEA1 protein to allow fluorophores to attach to specific   
   protein regions. This modification would make it easier to characterize   
   the protein structure and the changes that can occur when it interacts   
   with Rab5," explains Joan Antoni.   
      
   Armed with the suitable protein molecules and the valuable support of   
   co-author Janelle Lauer, a senior postdoctoral researcher in Marino   
   Zerial's research group, Joan and Anupam were able characterize the   
   dynamics of EEA1 thoroughly using the advanced laser scanning microscopes   
   provided by the light microscopy facilities at the MPI-CBG and the   
   NCBS. Strikingly, they discovered that the EEA1 protein could undergo   
   multiple flexibility transition cycles, from rigid to flexible and back   
   again, driven solely by the chemical energy released by its interaction   
   with the GTPase Rab5. These experiments showed that EEA1 and Rab5 form a   
   GTP-driven two-component motor. To interpret the results, Marcus Jahnel,   
   one of the corresponding authors and research group leader at PoL and   
   BIOTEC, developed a new physical model to describe the coupling between   
   chemical and mechanical steps in the motor cycle. Together with Stephan   
   Grill and Shashi Thutupalli, the biophysicists were also able to calculate   
   the thermodynamic efficiency of the new motor system, which is comparable   
   to that of conventional ATP-driven motor proteins.   
      
   "Our results show that the proteins EEA1 and Rab5 work together as a two-   
   component molecular motor system that can transfer chemical energy into   
   mechanical work. As a result, they can play active mechanical roles in   
   membrane trafficking. It is possible that the force-generating molecular   
   motor mechanism may be conserved across other molecules and used by   
   several other cellular compartments," Marino Zerial summarizes the   
   study. Marcus Jahnel adds: "I am delighted that we could finally test   
   the idea of an EEA1-Rab5 motor. It's great to see it confirmed by these   
   new experiments. Most molecular motors use a common type of cellular   
   fuel called ATP. Small GTPases consume another type of fuel, GTP, and   
   have been thought of mainly as signaling molecules. That they can also   
   drive a molecular system to generate forces and move things around puts   
   these abundant molecules in an interesting new light." Stephan Grill   
   is equally excited: "It's a new class of molecular motors! This one   
   doesn't move around like the kinesin motor that transports cargo along   
   microtubules but performs work while staying in place. It's a bit like   
   the tentacles of an octopus."  "The model we used is inspired by that   
   of the classical Stirling engine cycle.   
      
   While the traditional Stirling engine generates mechanical work by   
   expanding and compressing gas, the two-component motor described uses   
   proteins as the working substrate, with protein flexibility changes   
   resulting in force generation. As a result, this type of mechanism opens   
   up new possibilities for the development of synthetic protein engines,"   
   adds Shashi Thutupalli.   
      
   Overall, the authors hope that this new interdisciplinary study could   
   open new research avenues in both molecular cell biology and biophysics.   
      
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   Story Source: Materials provided by Technische_Universita"t_Dresden. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Anupam Singh, Joan Antoni Soler, Janelle Lauer, Stephan W. Grill,   
      Marcus   
         Jahnel, Marino Zerial, Shashi Thutupalli. Two-component molecular   
         motor driven by a GTPase cycle. Nature Physics, 2023; DOI:   
         10.1038/s41567-023- 02009-3   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230504121009.htm   
      
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