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
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy