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September 5, 2014

Bacterial Garbage Removal Process Provides New-Antibiotic Target

  • A collaborative team of scientists from the University of Massachusetts-Amherst and the University of California-Berkeley reports that it has reconstructed how bacteria tightly control their cell cycle by specifically destroying key proteins through regulated protein degradation. This process
    uses energy-dependent proteases to selective destroy certain targets.

    Because regulated protein degradation is critical for bacterial virulence and invasion, understanding how these proteases function should help to uncover pathways that can be targeted by new antibiotics, according to the researchers.

    All organisms use controlled degradation of specific proteins to alter cellular behavior in response to internal or external cues, said Peter Chien, Ph.D., an assistant professor of biochemistry and molecular biology at U of M, Amherst. And, a process that has to happen as reliably and stably as cell division also has to be flexible enough to allow the organism to grow and respond to its ever-changing environment, he continued, adding that little has been known about the molecular mechanics of how cells meet these challenges.

    The team’s study (“Cell cycle-dependent adaptor complex for ClpXP-mediated proteolysis directly integrates phosphorylation and second messenger signals”) was published in PNAS.

    Energy-dependent proteases can be viewed as tiny molecular-level machines. By selectively cutting and destroying key proteins at precise time points during cell division, they take charge of when, and at what rate, a cell grows and divides. They are found in all kingdoms of life, but are especially important in bacteria where they help cells overcome stressful conditions such as an attack by antibiotic treatment.

    "When the environment becomes damaging, these proteases selectively target particular proteins to stop cell division so the bacteria can turn to focus instead on repair until the stress is over," explained Dr. Chien. "Understanding how bacteria use these machines at the cellular and molecular level could reveal avenues for discovery of new drugs to treat infectious diseases."

    The researchers focused on the bacterium Caulobacter crescentus. The cell cycle for this bacterium is controlled by the destruction of key proteins such as the essential transcription factor known as CtrA, but until now it has been unclear how this actually worked at the molecular level. Researchers have known for more than 20 years that one of the factors important for this protein destruction is an energy-dependent protease, ClpXP.

    But ClpXP is always present through the bacterial cell cycle, not always actively breaking down CtrA, suggesting that more complex regulation was going on. Further, more recent work showed that CtrA degradation requires changes in second messengers, small molecules that help different cell pathways communicate with each other. CtrA degradation also needs dephosphorylation of proteins known as adaptors.

    “We show that three proteins work together as a multicomponent adaptor to stimulate the degradation of a key regulatory protein, CtrA, in Caulobacter crescentus,” wrote the investigators. “The adaptor is only functional when one of the components, CpdR, is unphosphorylated and when another component, PopA, is bound to the signaling molecule cyclic diguanylate. These features ensure that CtrA is only proteolyzed during a specific window in the Caulobacter cell-division cycle.”

    Dr. Chien recently received a five-year, $1.4 million grant from NIH to further explore how bacteria deal with stress by destroying their own proteins. His future work should reveal new pathways that could be targeted to block bacterial virulence or to prevent bacteria from resisting the stresses produced by antibiotics now in use.

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