Researchers discover how a pair of proteins control cellular calcium signals

All mammalian cells need an immediate intake of calcium ions to perform functions as diverse as neurotransmission, muscle contraction, release of hormones or immune responses. This requirement is so fundamental that cells protect themselves from disasters by storing calcium in a network of intracellular cisterns called the endoplasmic reticulum or ER. Then, as the cells lose calcium as part of their daily routine, channels open up into the cell membrane, allowing calcium influx from the outside to fill the stores. RE and maintain cellular functions induced by calcium.

Patrick Hogan, Ph.D., and Aparna Gudlur, Ph.D., two researchers recently published by the investigator of the LaJolla Institute of Immunology (LJI). Cell reports and the other in the October 31, 2018 edition Nature Communications– Indicate how a calcium-sensing protein, called STIM1, signals that it is time to initiate calcium recovery, and then forwards this message to its partner, the calcium channel ORAI. This set of works lays the foundation for new methods of manipulating aberrant calcium signaling in the immune system, particularly in the context of autoimmune or inflammatory diseases.

"We have known for a decade that STIM1 protein has shifted to the plasma membrane to open up NIRS channels when calcium levels in REs are decreasing," says Hogan, a professor in the Division of Signaling and Disease. gene expression. "Our recent work shows how STIM machines work at the molecular level, and understanding these mechanisms is essential because calcium is important for a variety of immune responses."

the Cell reports The paper reveals how STIM1 protein lengthens when it goes from a rest state to an activated state when calcium stores decrease. STIM1 is a transmembrane protein that extends on the ER wall: one end pushes a calcium-sensitive gauge-like tail into the pool; in a state of rest and filled with calcium, the other arm comes out of the emergency room but remains pressed against the wall, away from the dormant ORA1 channels that dot the cell membrane.

The group defined what happens when calcium levels decrease by building and testing the behavior of genetically modified STIM1 proteins in cultured cells. An analysis showed that the loss of calcium from the sensor's tail caused the regions of two pairs of STIM1 proteins to be brought into the membrane inside the ER wall, pushing the outer arms to Extend to the cell membrane. This change in shape brought STIM1 close enough to the ORAI channels to open and open them, allowing calcium to flow back into the cells.

"The first article showed how STIM1 was communicating with a channel protein in the plasma membrane via a structural change," says Hogan. "Our last article takes this process back in time and shows how calcium loss in emergencies triggers this change."

In simple terms, the most recent document deals with the operation of the STIM1 calcium sensitive gauge. Previously, protein chemists discovered that the calcium contained in the ER bound to a structural motif of the STIM1 tail called "hand EF" and proposed that when the hand was empty, STIM1 activated ORAI. Gudlur, instructor at Hogan Lab and first author of the new paper, explains that it's not so simple. "We are now reporting that many calcium is linked not only to the EF hand but also to other sites in the STIM1 ER domain, and that the sites depend on each other," she said. "This revises the concept of STIM1 activation."

Not only that, but according to Hogan, the dominant belief was that the dissociation of calcium meant that the STIM1 gauge region inside the emergency room unfolded dramatically and assumed a chaotic structure, a disorder considered necessary for the activation of ORAI. "We now show that when calcium is low in the emergency, this region does not unfold but instead acquires a new but stable structure that promotes interaction with the ORAI channel," he says. "It's important because it means that the interaction could be targeted by inhibitors."

In fact, pharmaceutical companies have already sought to develop calcium channel blocking drugs in the ORAI to stop calcium-dependent immune responses in autoimmune diseases or inflammatory conditions such as acute pancreatitis. Some ORAI blocking drugs are currently undergoing Phase I and II clinical trials and seem so far nontoxic. But their therapeutic potential remains unknown.

Gudlur, who has played a leading role in both studies, speculates that the development of direct blockers of the ORAI / STIM1 as therapies might be only an initial step because the two proteins are common to many types of cells. "Targeting ORAI channels as a way to block excess calcium signaling in certain cells may require greater specificity," she explains. "Our work is a first step in identifying cell-specific factors that can modulate the activity of ORAI / STIM.1 Once we find them, screening tests targeting these factors would be needed."

Hogan recognizes that drug discovery is based on exploration. "People conducting basic research need to look at the fundamental cellular processes," he said, noting that more than 20 years had elapsed between the discovery of the CTLA4 immune control protein and approval by the FDA for blocking immune control as a treatment for melanoma. (Note: four days after this interview, the "discoverers" appointed by Hogan received the 2018 Nobel Prize in Physiology and Medicine). "If you do not tinker with the basics of a cell, you will never take a step forward.We do not always know where the treatments will come from."

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More information:
Aparna Gudlur et al, Calcium detection by the ER luminal domain of STIM1, Nature Communications (2018). DOI: 10.1038 / s41467-018-06816-8

Nupura Hirve et al. Coiled spiral formation transmits a STIM1 signal from ER light to cytoplasm, Cell reports (2018). DOI: 10.1016 / j.celrep.2017.12.030