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.


Facebook Twitter Pinterest LinkedIN Email

==========================================================================
FULL STORY ========================================================================== 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.

* RELATED_TOPICS
o Health_&_Medicine
# Nervous_System # Genes # Human_Biology #
Amyotrophic_Lateral_Sclerosis
o Plants_&_Animals
# Molecular_Biology # Genetics # Cell_Biology #
Biotechnology_and_Bioengineering
* RELATED_TERMS
o Chloroplast o Prokaryote o Methyl_tert-butyl_ether o
Molecular_biology o Autophagy o Hydroelectricity o Sled_dog
o Cell_membrane

========================================================================== Story Source: Materials provided by Technische_Universita"t_Dresden. Note: Content may be edited for style and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230504121009.htm

--- up 1 year, 9 weeks, 3 days, 10 hours, 52 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)