During their formation within the cells, many proteins rely on the assistance of molecular protectors, so-called chaperones. They help the proteins to fold correctly and thus ensure the right final structure. The roles of chaperones in membrane protein folding have long remained unclear. Researchers at the Biozentrum, University of Basel, and at ETH Zurich have now shown how chaperones stabilize an immature bacterial membrane protein and guide it in the right folding direction, thus protecting it from misfolding. Their study was recently published in “Nature Structural & Molecular Biology”.
Cellular machines continuously produce long polypeptide chains, the proteins. In order to properly fulfill its cellular function, a protein must however first adopt its correct spatial structure. In each cell there are molecular helper proteins called chaperones. They take care of the immature proteins to help them in the folding process and thus preventing errors.
The scientists led by Prof. Sebastian Hiller from the Biozentrum, University of Basel, and Prof. Daniel Müller from the Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich in Basel have discovered how two chaperones in the gut bacterium E. coli protect the membrane protein FhuA during transport and assist its insertion into the membrane.
Chaperones help insertion of membrane protein
Countless proteins, which transport nutrients and signaling molecules, are embedded in the outer membrane of bacteria. One of these membrane transporters is the protein FhuA. Via this protein, the bacteria take up vitally important iron but also antibiotics. But how does the very large, barrel-shaped FhuA protein reach the outer membrane intact? The scientists from the Biozentrum and the D-BSSE have investigated this process more deeply.
In order to reach its goal in the outer membrane, FhuA uses the help of several chaperones. Using structural analyses and single-molecule force spectroscopy, the researchers have now elucidated how these two chaperones stabilize the immature protein and prevent misfolding. “This process is extremely dynamic,” says Hiller.
“Under the protection of the chaperones, within a millisecond, FhuA constantly changes its structure. It thus explores energetically favorable conformations which enable the stepwise insertion and folding of individual protein segments into the membrane.” With the insertion of the final protein segment, FhuA acquires its mature and functional barrel structure. Left unprotected, FhuA would fold incorrectly and finally aggregate.
Protein chaos without chaperones
Chaperones are significantly involved in the formation of functional proteins. They play an important role in the correct folding of soluble proteins and furthermore are necessary for the insertion of membrane proteins into the bacterial outer membrane. Because several organelles in plant and animal cells are of bacterial origin, chaperones also protect their membrane proteins in a similar manner and assist during membrane insertion. The new findings are consequently of great relevance also for diseases caused by misfolded proteins such as Alzheimer's, Parkinson's or cystic fibrosis.
“It has been known for a long time that chaperones protect other proteins from misfolding and encourage them to fold correctly. Now, our work has succeeded in demonstrating – for the first time in biological membranes – how chaperones support the membrane proteins that are key to pharmaceutical research,” explains ETH Professor Daniel Müller. Until recently, these could almost only be investigated using artificial environments. However, this meant that there was barely any understanding of how proteins fold into a cell’s membrane.
“To give a loose analogy, until now it was like putting a cow on a sheet of ice in order to investigate its natural behaviour and then observing surprising reactions,” says Müller. “We now have a better understanding of how the cell incorporates its molecular machines into membranes so that they can perform their versatile duties.”
Johannes Thoma, Björn M Burmann, Sebastian Hiller & Daniel J Müller
Impact of holdase chaperones Skp and SurA on the folding of β-barrel outer-membrane proteins
Nature Structural & Molecular Biology (2015), doi: 10.1038/nsmb.3087
Prof. Sebastian Hiller, University of Basel, Biozentrum, tel. +41 61 267 20 82, email: firstname.lastname@example.org
Prof. Daniel J. Müller, ETH Zurich, Department of Biosystems Science and Engineering, tel. +41 61 387 33 07, email: email@example.com
Katrin Bühler | Universität Basel
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction