Physics and biology team up to tackle protein folding debate
A team of researchers from EPFL, (Ecole Polytechnique Fédérale de Lausanne), the University of Lausanne, Northwestern University and Tel Aviv University bring biology and statistical physics together to answer the question of how molecular chaperones fold, unfold and pull proteins around in the cell. Their results appear the week of April 3 in the advance online edition of the Proceedings of the National Academy of Sciences.
A series of discussions in a campus café in Lausanne has blossomed into an extraordinary collaboration between EPFL physics professor Paolo De Los Rios and University of Lausanne biology professor Pierre Goloubinoff. Using the principles of statistical physics, they have identified a simple, single mechanism that explains the mechanical role of molecular chaperones in protein folding and translocation, settling at the same time a long-standing controversy over this process.
Molecular chaperones are specialized proteins that help other proteins find their proper conformations and reach their proper places in the cell. For more than two decades, biologists and biochemists have debated how one of these chaperones, Hsp70, manages the mechanical job of unfolding protein aggregates and pulling proteins into the various compartments of the cell. Is it by a “Power Stroke”, in which the chaperone would use leverage and produce a mechanical force that pulls the protein, or a “Brownian Ratchet”, in which the presence of the chaperone and the thermal fluctuations of the protein itself combine to pull the protein? There is no overwhelming evidence in favor of one explanation over the other. More importantly, neither theory explains the full range of Hsp70’s activity.
Using their prior results from biochemistry, De Los Rios and Goloubinoff turned to molecular geometry, statistical physics and the laws of thermodynamics in an attempt to solve the problem. The result, which they have dubbed “Entropic Pulling”, is a modified form of the Brownian Ratchet mechanism. Molecular systems, they explain, must obey the laws of physics and strive for equilibrium. In the process, they increase their entropy. When the Hsp70 molecule, attached to a protein, hits a membrane or an aggregate, a tiny force due to entropy pushes it away again, dragging the protein strand along with it. The collaborators demonstrated that this entropic effect, combined with the protein’s own thermal fluctuations, can exert enough force to pull a protein through the narrow pore of a mitochondrial membrane or disentangle an aggregate in the cell.
“Our explanation is so simple,” De Los Rios says, “that it almost seems disappointing. We have shown that all the functions of Hsp70 in the cell can be explained by one simple mechanism.”
Many diseases – among them mad cow, Parkinsons and Alzheimer’s diseases -- are caused by misfolded proteins or aggregates. Goloubinoff emphasizes that understanding how chaperones such as Hsp70 function is important groundwork that must be laid before we can hope to develop strategies to treat these kinds of protein-misfolding pathologies.
Simple, elegant solutions often belie the struggle that went into their creation. The collaborators invested much time, energy (and coffee!) becoming familiar with the culture and language of each other’s discipline. Now the effort has borne fruit in an excellent demonstration of the potential of interdisciplinary research in physics and biology.
Mary Parlange | alfa
The most recent press releases about innovation >>>
Die letzten 5 Focus-News des innovations-reports im Überblick:
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
Researchers from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, the Italian Space Agency (ASI), and the Instituto Geofisico--Escuela Politecnica Nacional (IGEPN) of Ecuador, showed an increasing volcanic danger on Cotopaxi in Ecuador using a powerful technique known as Interferometric Synthetic Aperture Radar (InSAR).
The Andes region in which Cotopaxi volcano is located is known to contain some of the world's most serious volcanic hazard. A mid- to large-size eruption has...