Ion channel with bouncer: Calcium ions block channel opening depending on pH value
Biochemists discover ring structure at opening of ion channel TRPML2, which can be closed by calcium ions
Ion channels are pores in the membrane of cells or cell organelles that enable the transport of positively or negatively charged particles, so-called ions, through these membranes. Biochemists at the Johannes Gutenberg University in Mainz (JGU) have now for the first time taken a high-resolution look at the human calcium ion channel TRPML2 and the structure of a large ring on one side of the membrane. This ring acts as a doorman and decides on the opening or closing of the ion transport pathway. "With our study, we were able to show for the first time what the structure of the ring, also known as extracellular/lumenal domain, looks like in human TRPML2 and that it is responsible for the interaction with calcium," explains junior professor Dr. Ute Hellmich from the Institute of Pharmacy and Biochemistry - Therapeutic Life Sciences at JGU. Depending on the pH value, the calcium ions can open or block the passage so that they can no longer pass through.
Junior Prof. Dr. Ute Hellmich's research group investigated the structural properties of the ion channel that are responsible for the passage of calcium ions. "Calcium is an important cellular signal that also plays a role in many diseases," said Hellmich. The element performs numerous tasks in the body, including regulating enzymes and helping with membrane fusions.
TRPML2, which stands for "Transient Receptor Potential Mucolipin", is an ion channel of the mucolipin subfamily of TRP channels that are relevant for sensory perception in humans. Among other things, TRPML2 plays a role in the immune response to infections and increases the infectivity of zika and dengue viruses. Mutations in TRPML ion channels also lead to blindness, deafness and neurological damage in humans.
pH value decisive for ion channel activity
As Hellmich makes clear, ion channels are not simply a hole or a pore, but the channels open and close. This in turn determines whether and how cellular processes take place. "In TRPML2, we have now discovered that the extracellular/lumenal domain, which is located on top of the channel, binds calcium depending on the pH value," explains Kerstin Viet, first author of the publication in the journal Structure. She carried out the investigations as part of her master's thesis and received the Adolf Todt Foundation Prize for her work.
At a high pH value, i.e. at a value of about 7 outside the cell, the calcium ions can couple to the ring and thus close it. Conversely, the calcium ions are no longer able to lock the opening when the pH value is low, as is the case in certain intracellular compartments. "The ring functions like a doorman for the rest of the ion channel," said Viet describing the task.
The ion channel is only supposed to be active inside the cell, where a low pH value prevails, or become active when a certain signal in the cell requires calcium. If it were also active on the cell surface, this could lead to cell damage. "This is quite cleverly regulated and important for the cell's reaction to a viral infection," said Hellmich, pointing out that the entire process of when and how an ion channel is opened or closed is not yet well understood. The other two ion channels of the human mucolipin subfamily, TRPML1 and TRPML3, also have such a bouncer ring, so that the three species can now be compared with each other for the first time.
The first structural information on the ion channel TRPML2 was presented by the Membrane Biochemistry working group in close cooperation with Prof. Dr. Tanja Schirmeister's working group in Pharmacy at the Johannes Gutenberg University in Mainz, scientists from the European Synchrotron Radiation Facility (ESRF) in Grenoble and the working groups of junior Prof. Dr. Nina Morgner, Goethe University in Frankfurt, and Prof. Dr. Hermann Schindelin, University of Wurzburg.
