May 19, 1999 In an effort to solve the mystery of how cells "decide" when and where to move, scientists have uncovered a molecular strategy evolved in mammals to assure tight control of cellular marching orders. But the two-pronged approach appears to be exploited by a pathogenic microbe that hijacks the cell's molecular motors to power a destructive march through its human host.
The research by biochemists at the University of California San Francisco is reported in the May 14 issue of the journal Cell.
Regulated movement at the cellular level is critical for survival. Cells divide, migrate toward food and away from danger. Nerve axons grow and immune armies attack -- all in response to orders from a family of molecules known as organizing or signaling proteins. These proteins are thought to translate selected signals into commands that engage the cell's gears of motion.
The pathogenic, food-borne bacterium Listeria monocytogenes, which can cause meningitis and other serious illnesses, is known to recruit the motility apparatus of its human host cells. It uses this engine to power arocket-like tail and propel itself along a route of infection from one cell to the next.
By studying the three-dimensional structure of a mouse organizing protein called "Enabled" and analyzing its chemical interactions with one of Listeria's proteins, the UCSF scientists found that the microbe's success may lie in its ability to mimic a dual molecular docking maneuver that takes place in mammalian cells, most likely evolved to reduce the chance the cells will march to the wrong orders.
Under normal conditions, the Enabled protein links to receptors near the cell membrane when it receives an external signal to move. Then the organizing protein recruits and mobilizes the cell's motility protein, actin. The cell will then move in the direction that corresponds to the buildup of actin.
The researchers found that in addition to its chemical and structural attraction to the receptor, Enabled also appears to be simultaneously attracted to cell membrane molecules known as phospholipids. They found that a positively charged region of the Enabled protein is drawn to the negative charge of the phospholipids. This dual control - through Enabled's attraction to both the receptor protein and the membrane phospholipids -- could greatly increase the reliability of the marching orders, the researchers suggest, just as if a command to attack had to be confirmed by two different officers in the field before soldiers were committed to advance.
"Our examination of the structure of Enabled shows that this organizing protein is built to interact with multiple partners," said Wendell Lim, PhD, assistant professor of molecular and cellular pharmacology at UCSF and senior author on the paper in Cell. "Requiring dual inputs for activation allows more controlled and precise cellular movements," an evolutionary advantage over a more error-prone one-signal system.
The researchers also discovered that Listeria is able to mimic both cellular aspects that attract Enabled. The microbe presents multiple copies of a protein very similar to the normal cellular receptor that binds Enabled, making itself even more attractive to Enabled than the cell's normal receptor is. In addition, the microbe posseses a "negatively charged tail," which attracts the positive charged region of EVH1 more strongly than do the membrane phospholipids.
Taken together, these Listeria biochemical traits so successfully mimic the cell's normal strategy to bind EVH1, that the molecule has 100 times greater affinity to the bacterium than it does to its own evolved binding partners.
With this enhanced ability to recruit the organizing protein, Listeria can efficiently hijack the human cell's own motility protein, actin. Powered by actin, Listeria microbes blast through their host cells like erratic torpedoes, leaving infection in their wake.
"Listeria appears to emulate the multiple signals that are normally used in mammalian cells to activate Enabled, but does so with a single, tighter binding molecule," said Kenneth E. Prehoda, PhD, postdoctoral fellow in Lim's laboratory and lead author on the study. "So, while normal cell movements are delicate and highly regulated, Listeria harnesses the cell's engine at full-throttle."
Understanding how proteins like Enabled are activated, both in normal cells and by pathogens like Listeria may aid in the development of treatments for infections, metastatic cancer, inflammation, and developmental diseases, Lim and Prehoda say.
Do J. Lee, staff research associate in the UCSF laboratory, also participated in the research and co-authored the Cell paper.
The research is funded by the National Institutes of Health, the Howard Hughes Medical Institute Research Resources Program, The Burroughs Welcome Young Investigator Program, the Searle Scholars Program, and the Packard Foundation.
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