Japanese scientists have discovered how a protein called Xkr4 is activated by calcium ions to signal immune cells to help them clean up dying cells. This finding shows a unique role for calcium in cell membranes and could provide new insights into cellular cleanup mechanisms. The scientists discovered that extracellular calcium mediates the activation of a membrane protein that waves a flag that signals cell death.
A research team co-led by scientists from the Institute for Integrated Cell-Materials Science (iCeMS) at Kyoto University in Japan has revealed the mechanism of how dying cells activate a protein that triggers an "eat me" signal from immune cells to clean up cellular debris. These findings were recently published in the journal Nature Communications.
This protein is called Xkr4 and is one of the Xkr family proteins in the cell membrane. Xkr4 disrupts the phospholipid phosphatidylserine from the inside of the cell membrane (normally located inside the cell membrane) to the outside of the cell membrane. The transfer of phosphatidylserine to the outside of the cell membrane is a signal that the cell is about to die and is also a signal that attracts phagocytes to engulf debris.
Xkr4 activation process
The researchers previously found that to become a phosphatidylserine disruptor, the C-terminal cytoplasmic tail of Xkr4 must first be cleaved to form a dimer with another Xkr4 and expose a binding site. This binding site is then linked to another protein fragment called XRCC4.
However, in experimental settings, the binding of XRCC4 to Xkr4 alone is not sufficient to activate Xkr4. This suggests that other ingredients are needed.
The role of calcium ions
The Japanese research team found that calcium ions are necessary to activate Xkr4. Positively charged calcium ions outside the cellular environment bind to three negatively charged amino acids on the two "helices" of the Xkr4 protein. This combination takes Xkr4 from an intermediate state to a fully activated state.
"We found that extracellular calcium acts as a molecular glue for the Xkr4 transmembrane helix, activating Xkr4," explains iCeMS biochemist Jun Suzuki.
Unexpected effects of calcium and future research
Surprisingly, extracellular calcium is known to be involved in regulating the activity of proteins in the intracellular and extracellular environment, but not the cell membrane itself. "We unexpectedly discovered that extracellular calcium penetrates the transmembrane region of the protein and connects the two transmembrane helices," Suzuki said.
The study also suggests that calcium ions may be important for activating other members of the Xkr protein family, specifically Xkr8 and Xkr9, which could help elucidate the mechanism of action of these and other scrambled enzyme proteins.
The team's next steps will be to study the function of Xkr4 in nerve cells and explore their role in the brain.
Reference Panpan Zhang, Masahiro Maruoka, Ryo Suzuki, Hikaru Katani, Yu Dou, Daniel M. Packwood, Hidetaka Kosako, Motomu Tanaka and Jun Suzuki published in Nature Communications on September 11, 2023: "Extracellular calcium acts as a molecular adhesive for transmembrane helices to activate disruptor Xkr4"
DOI:10.1038/s41467-023-40934-2
Compiled source: ScitechDaily