Biochemists identified the structure of a ring located at the opening of the TRPML2 ion channel that can be blocked by calcium ions
Ion channels are pores in the membrane of cells or cell organelles. They allow positively or negatively charged particles, so-called ions, to be transported across the membrane. Biochemists at Johannes Gutenberg University Mainz (JGU) have now succeeded in imaging an important regulatory region of the human TRPML2 calcium ion channel at high resolution, an area of the channel shaped like a large ring on one side of the membrane.
This ring acts like a doorman, deciding whether ions can move through the channel. "Our study has revealed the structure of the ring, which is also called the extracytosolic/lumenal domain (ELD), in human TRPML2 channels, and also that it is this domain that is responsible for the channel's interaction with calcium," said Professor Ute Hellmich of the JGU Institute of Pharmacy and Biochemistry – Therapeutical Life Sciences.
Depending on the pH value, the calcium ions can open or block the channel, and therefore control their transport across cellular membranes.
Hellmich's research group investigated which structural properties of the ion channel ring are responsible for allowing calcium ions to pass. "Calcium is an important cellular messenger that also plays a role in many diseases," explained Hellmich. The element performs numerous tasks in the body, including regulating enzymes and helping with membrane fusion.
TRPML2, short for transient receptor potential mucolipin 2, is an ion channel of the mucolipin subfamily of TRP channels involved in sensory perception in humans. TRPML2 plays a role in the immune response to infections and increases the infectivity of Zika and dengue viruses. In addition, mutations in TRPML ion channels can result in blindness, deafness, and neurological damage in humans.
The pH value is crucial for ion channel activity
As Hellmich makes clear, ion channels are not simple holes. They can be actively opened and closed. This, in turn, activates and controls cellular pathways. "We have now discovered that binding of calcium to the TRPML2 extracytosolic/lumenal domain on top of the channel is dependent on pH," stated Kerstin Viet, first author of the paper in the scientific journal Structure. This research was part of her Master's thesis and resulted in her being awarded the Adolf Todt Foundation Prize.
At a higher pH value of around 7, found at the outside of the cell, the calcium ions can bind to the ring and thus block it. Conversely, the calcium ions are no longer able to block the opening at a lower pH typical of certain intracellular compartments. "The ring acts like a gatekeeper for the rest of the ion channel," said Viet.
This therefore regulates the activity of the channel: It is important that the ion channel is only activated within the cell, where the pH is generally low; in effect the channel is only opened when a particular cellular mechanism signals that it requires calcium. Unprompted activation on the cell surface could well result in damage to the cell.
"The regulation mechanism is clever. It is also relevant, for example, to how the cell reacts to a viral infection," said Hellmich, adding that the entire process just when and how an ion channel is opened or closed is not yet fully understood. The other two ion channels of the human mucolipin subfamily, TRPML1 and TRPML3, also have a similar doorkeeper ring. The study's results therefore make it possible for the first time to compare all three subtypes.
This first identification of the structure of the ion channel TRPML2 was achieved by the Membrane Biochemistry group of Professor Ute Hellmich working in close cooperation with the JGU Pharmacy group of Professor Tanja Schirmeister. They also collaborated with scientists from the European Synchrotron Radiation Facility (ESRF) in Grenoble, and the working groups of Professor Nina Morgner of Goethe University Frankfurt and Professor Hermann Schindelin of Julius-Maximilians-Universität Würzburg.
A doorkeeper ring: The extracytosolic/lumenal domain of the human TRPML2 ion channel, whose structure the present study elucidated for the first time, functions as a pH-dependent calcium controller. It regulates the function of the channel in different cellular compartments.
Ill./©: Kerstin K. Viet
Junior Professor Dr. Ute Hellmich
Institute of Pharmacy and Biochemistry – Therapeutic Life Sciences
Johannes Gutenberg University Mainz
55099 Mainz, GERMANY
phone +49 6131 39-26182
fax +49 6131 39-25348
K. K. Viet et al., Structure of the Human TRPML2 Ion Channel Extracytosolic/Lumenal Domain, Structure, 6 June 2019,
https://www.blogs.uni-mainz.de/fb09hellmich/membrane-biochemistry/ – Workgroup Hellmich: Membrane Biochemistry
http://www.uni-mainz.de/presse/aktuell/7661_ENG_HTML.php – press release "New therapeutic approach to combat African sleeping sickness" (20 Feb. 2019)
Petra Giegerich | idw - Informationsdienst Wissenschaft
If Machines Could Smell ...
19.07.2019 | Fraunhofer-Institut für Produktionstechnik und Automatisierung IPA
Algae-killing viruses spur nutrient recycling in oceans
18.07.2019 | Rutgers University
Adjusting the thermal conductivity of materials is one of the challenges nanoscience is currently facing. Together with colleagues from the Netherlands and Spain, researchers from the University of Basel have shown that the atomic vibrations that determine heat generation in nanowires can be controlled through the arrangement of atoms alone. The scientists will publish the results shortly in the journal Nano Letters.
In the electronics and computer industry, components are becoming ever smaller and more powerful. However, there are problems with the heat generation. It is...
Scientists have visualised the electronic structure in a microelectronic device for the first time, opening up opportunities for finely-tuned high performance electronic devices.
Physicists from the University of Warwick and the University of Washington have developed a technique to measure the energy and momentum of electrons in...
Scientists at the University Würzburg and University Hospital of Würzburg found that megakaryocytes act as “bouncers” and thus modulate bone marrow niche properties and cell migration dynamics. The study was published in July in the Journal “Haematologica”.
Hematopoiesis is the process of forming blood cells, which occurs predominantly in the bone marrow. The bone marrow produces all types of blood cells: red...
For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.
Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...
An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".
The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...
24.06.2019 | Event News
29.04.2019 | Event News
17.04.2019 | Event News
19.07.2019 | Physics and Astronomy
19.07.2019 | Physics and Astronomy
19.07.2019 | Earth Sciences