Signaling within cells is compartmentalized!

Signaling within cells is compartmentalized!

Research results reported in the journal Science overturn long-held views on a basic messaging system within living cells.

The researchers explained that key cellular communication machinery is more regionally constrained inside the cell than was previously thought. Communication via this vital system is akin to social networking on your Snapchat account.

Within a cell, the precise positioning of such messaging components allows hormones, the body's chief chemical communicators, to transmit information to exact places inside the cell. Accurate and very local activation of the enzyme that Scott and his group study helps assure a correct response occurs in the right place and at the right time.

"The inside of a cell is like a crowded city," said the senior author, "It is a place of construction and tearing down, goods being transported and trash being recycled, countless messages, (such as the ones we have discovered), assembly lines flowing, and packages moving. Strategically switching on signaling enzyme islands allows these biochemical activities to keep the cell alive and is important to protect against the onset of chronic diseases such as diabetes, heart disease and certain cancers."

Many hormone receptors stimulate production of cyclic AMP (adenosine monophosphate), which activates PKA (protein kinase A). The textbook view suggests that activation releases the catalytic subunit of the enzyme from its complex with the regulatory subunit.

Researchers closely monitored activation of PKA using electron microscopy and native mass spectrometry and found that dissociation of the holoenzyme was not necessary for activation. The kinase, which binds anchoring proteins that localize it in the cell, appears to be restricted to acting within about 200 Å of such anchoring proteins. Parts of the molecule are flexible, allowing it to both contract and stretch, with floppy arms that can reach out to find appropriate targets. Still, where the molecule performs its act, space is tight. The distance is, in fact, about the width of two proteins inside the cell. Thus, PKA activity is more precisely targeted within the cell than previously anticipated.

"We realize that in designing drugs to reach such targets that they will have to work within very narrow confines, "senior author said.

One of his group's collective goals is figuring out how to deliver precision drugs to the right address within this teeming cytoplasmic metropolis.

"Insulating the signal so that the drug effect can't happen elsewhere in the cell is an equally important aspect of drug development because it could greatly reduce side effects," senior author said.