The secret life of proteins: Researchers discover dual role of key player in immune system

That protein, STIM1, was previously known to sense a change in calcium within immune cells, a process that occurs when the body confronts a pathogen. Upon sensing this change, STIM1 opens a type of pore in the cell membrane, called a CRAC channel, to allow the flow of calcium ions — a vital step in activating the immune system.

The Feinberg team, led by Murali Prakriya, assistant professor of molecular pharmacology and biological chemistry, discovered that STIM1 not only opens these pores but is responsible for determining the exquisite selectivity for calcium ions within the CRAC channels, a critical factor in kick starting the body's immune system. These findings were recently reported in the journal Nature.

"People have generally thought that selectivity of ion channels is fixed and that selectivity and opening are separate processes; this is a fundamental shift in the way scientists believe ion channels operate," says Prakriya, referring to the 'pores' that STIM1 regulates. "CRAC channels and STIM1 are absolutely vital to activating the immune system. As is observed in some human patients, you can block key parts of the system by blocking these molecules in immune cells. These finding reveal not only a novel mechanism by which CRAC channels operate, but also new ways in which it encodes biological information. This represents exciting new possibilities to develop therapeutics to treat a broad range of conditions."

To determine that STIM1 is responsible for selectivity and opening, the researchers created a mutated CRAC channel designed to keep the pore open without the assistance of STIM1. When the channel was opened without STIM1, multiple types of ions were passed through the pore, including sodium and potassium. When STIM1 was added back in, the channel became very selective for calcium ions again, like the normal channel. Even at low doses of STIM1, the unmutated channel lost its normally high calcium selectivity, allowing the entry of multiple types of ions.

Conditions that might benefit from immune suppression are likely targets for future CRAC channel targeted therapy, including autoimmune diseases and many types of allergies. Additionally, targeting CRAC channels could provide improvements for existing immune suppression therapies such as those used during transplantation.

"The CRAC channel is emerging to be incredibly important for the immune system," says Prakriya. "But we have been solely focused on its calcium conducting mode that occurs in response to STIM1. It is certainly possible that there could be other players in the cell that open the CRAC channel pore to permit the flux of other ions to stimulate different cell functions. That's the next question."

Also in the Nature article, Prakriya's team identified the location of the barrier, or gate, within the CRAC channel that controls its opening and closing.

"The identification of the molecular and structural regions of the pore that controls opening and closing is highly valuable for facilitating drug design targeting CRAC channels for the treatment of immune disorders," he adds.

Provided by Northwestern University (news : web)

Envelope for an artificial cell

Neal Devaraj, assistant professor of chemistry at the University of California, San Diego, and Itay Budin, a graduate student at Harvard University, report their success in the Journal of the American Chemical Society.

“One of our long term, very ambitious goals is to try to make an artificial cell, a synthetic living unit from the bottom up – to make a living organism from non-living molecules that have never been through or touched a living organism,” Devaraj said. “Presumably this occurred at some point in the past. Otherwise life wouldn’t exist.”

By assembling an essential component of earthly life with no biological precursors, they hope to illuminate life’s origins.

“We don’t understand this really fundamental step in our existence, which is how non-living matter went to living matter,” Devaraj said. “So this is a really ripe area to try to understand what knowledge we lack about how that transition might have occurred. That could teach us a lot – even the basic chemical, biological principles that are necessary for life.”

Molecules that make up cell membranes have heads that mix easily with water and tails that repel it. In water, they form a double layer with heads out and tails in, a barrier that sequesters the contents of the cell.

Devaraj and Budin created similar molecules with a novel reaction that joins two chains of lipids. Nature uses complex enzymes that are themselves embedded in membranes to accomplish this, making it hard to understand how the very first membranes came to be.

“In our system, we use a sort of primitive catalyst, a very simple metal ion,” Devaraj said. “The reaction itself is completely artificial. There’s no biological equivalent of this chemical reaction. This is how you could have a de novo formation of membranes.”

They created the synthetic membranes from a watery emulsion of an oil and a detergent. Alone it’s stable. Add copper ions and sturdy vesicles and tubules begin to bud off the oil droplets. After 24 hours, the oil droplets are gone, “consumed” by the self-assembling membranes.

Although other scientists recently announced the creation of a “synthetic cell,” only its genome was artificial. The rest was a hijacked bacterial cell. Fully artificial life will require the union of both an information-carrying genome and a three-dimensional structure to house it.

The real value of this discovery might reside in its simplicity. From commercially available precursors, the scientists needed just one preparatory step to create each starting lipid chain.

“It’s trivial and can be done in a day,” Devaraj said. “New people who join the lab can make membranes from day one.”

Provided by University of California - San Diego (news : web)