Professor Claudio Grosman and research scientist Gisela Cymes published their work in the journal Nature.
Nicotinic-type receptors are proteins embedded in the membranes of nerve and muscle cells that regulate activity. A neurotransmitter, such as acetylcholine, triggers a small conformation change in the protein that opens a channel and allows ions to flow into the cell. These receptors are key players in muscle motion and neurological diseases such as epilepsy.
The protein family is divided into two classes, with very similar structure but different function: One mediates inhibition by channeling anions, or negatively charged ions, while the other mediates excitation by channeling positively charged cations.
“This is the yin and yang of the central nervous system,” said Grosman, a professor of molecular and integrative physiology, of biophysics and of neuroscience. “The anion members of the family and the cation members of the family pretty much look the same. The overall structure is the same. So, the question is, what is the reason for the different charge selectivity?”
The team focused on the segment of protein lining the inside of the channel. The two types of channels display very small differences in their sequence of amino acids, the building blocks of proteins. Both the anion-selective and cation-selective channels have a ring of basic amino acids, lysine or arginine, which generally carry a positive charge. This makes sense for an anion-selective channel, but raises some questions about why cations are not repelled by these positive charges.
The charge of amino acid residues is a fundamental aspect of protein function and structure. In order to model proteins computationally, researchers have to assign a charge to each residue, so they rely on the charge the amino acid would display in bulk water – for example, assuming that basic residues are always positively charged. However, proteins offer a much more complex environment, and it can be difficult for researchers to determine whether a particular amino acid has accepted or lost a proton to become charged.
Grosman and Cymes use an approach called patch-clamp recording, a single-molecule technique that allows them to measure binding and unbinding of single protons in functioning molecules, something that other powerful approaches cannot achieve.
With patch-clamp recording, the researchers could see the charge state of working ion channels in living cells. They saw that, in anion-selective channels, the basic residues appear to have the expected positive charge. However, in the cation-selective channels, the lysine or arginine seems to be tucked into the protein structure so that it cannot accept a proton from the surrounding environment and instead remains neutral. This allows cation-selective channels to keep the basic residues in their sequential place without having to substitute them with other amino acids.
“These channels are the subject of a lot of computational studies. Before this paper, if researchers had to model these channels, they would always run the simulation with all the ionizable residues charged, and the simulation could well be wrong,” Grosman said. “With small tweaks, changing the position of the amino acid changes its properties. For a lysine to be protonated or deprotonated is a big difference. It’s not trivial.”
“Overall, we want to emphasize the notion that the properties of these chargeable amino acids depends strongly on their particular microenvironment in the whole protein,” Grosman added.
While the study focused on muscle acetylcholine receptors, Grosman believes the “tucked-in” principle holds true for the entire superfamily of nicotinic-type receptors. Next, they plan to use the patch-clamp technique to further investigate the amino acids neighboring the lysine or arginine to gain a greater understanding of how this class of proteins regulates inhibition and excitation.
“This approach has opened a window and we can start understanding things that were intractable until now,” said Grosman. “This is important because it brings us closer to what the protein actually looks like if we want to understand how it works.”
This work was supported by the National Institutes of Health.
Liz Ahlberg | University of Illinois
Further information:
http://www.illinois.edu
Further reports about: > Big Bang > Channels > Ionen > Small Molecule > amino acid > building block > living cell > neurological disease
Rochester scientists discover gene controlling genetic recombination rates
23.04.2018 | University of Rochester
One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.
Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...
Anzeige
Anzeige
Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"
13.04.2018 | Event News
Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018
12.04.2018 | Event News
IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur
09.04.2018 | Event News
Tiny microenvironments in the ocean hold clues to global nitrogen cycle
23.04.2018 | Earth Sciences
Joining metals without welding
23.04.2018 | Trade Fair News
Researchers illuminate the path to a new era of microelectronics
23.04.2018 | Information Technology