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Van Andel Research Institute Study Provides New Details Of Fundamental Cellular Process

January 24, 2012

Study of plant hormone could have far-reaching implications for cell biology and disease research

A recent Van Andel Research Institute (VARI) study published in the journal Science investigating the molecular structure and function of an essential plant hormone could profoundly change our understanding of a key cell process, and might ultimately lead to the development of new drugs for a variety of diseases.

The study builds on earlier work by the same team of investigators at VARI that was published in the journal Nature in 2009. That study shed light on how plants respond when they are under stress from extreme temperatures, drought and other harsh environmental conditions and was later named by Science as one of the top scientific breakthroughs of 2009.

Understanding how cells talk

In signal transduction — the basic process of intercellular and intracellular communication — enzymes known as kinases and phosphatases serve as the opposing partners and key regulators of this process.

VARI scientists mapping the structure of the receptor for Abscisic acid (ABA), a plant hormone that controls growth, development and responses to environmental stress, discovered that ABA regulates the stress-response pathway by affecting an enzyme belonging to the phosphatase family – which in turn binds to a kinase.

“This process has been little understood,” said Karsten Melcher, Ph.D., Head of the VARI Laboratory of Structural Biology and Biochemistry and co-author of the study. “We believe that the activation mechanism may in many cases also be structural. Phosphatases inactivate the active site like a plug — changing the shape of the kinase.”

“The textbook assumption has been that enzymatic phosphatases inhibit kinases only by taking away phosphates from the kinases. There have been few recorded examples of non-enzymatic phosphatases inhibiting kinases.”

Knowing that these enzymes mimic the structure of the opposing enzyme enables scientists to more accurately develop mechanisms to activate or inhibit intercellular and intracellular communication. Inhibiting or activating this process in plant cells could lead to plants that more readily survive drought or other conditions of stress.

Possible impact on the treatment of diseases

In mammalian cells the ability to impact communication has numerous and far-reaching implications.  For example, applications that inhibit or activate cell communication in out-of-control metastasizing cancer cells have enormous potential to affect tumor growth.

Writing in the journal Science, where the study was published on January 6, Jeffrey Leung notes that “molecular mimicry might be a common mechanism in many biological processes involving kinase-phosphatase complexes“¦The structural studies on the core ABA signaling proteins establish a new paradigm for kinase-phosphatase co-regulation and coevolution.”

The possibility of broader scientific implications is also noted by Melcher.

“The current studies take a step back from application and focus back on fundamental cellular mechanisms with a broad implication beyond ABA signaling,” said Melcher.

In their 2009 study in Nature, Melcher and H. Eric Xu, Ph.D., used X-ray crystallography to detail precisely how ABA works at the molecular level. One of ABA´s effects is to cause plant pores to close when plants are stressed so that they can retain as much water as possible.

In a follow-up 2010 study published in Nature Structural & Molecular Biology, the VARI team identified several synthetic compounds that fit well with ABA´s many receptors to have the same effect.  By finding compounds that can close these pores, researchers´ findings could lead to sprays that use a plant´s natural defenses to help it survive harsh environmental conditions.

“This type of finding once again demonstrates the importance of identifying, mapping and understanding fundamental cellular and molecular processes because of the profound implications for human health,” said Xu, Director of the VARI Center for Structural Biology and Drug Discovery and co-author of the current Science study.  “Proteins with similarities to plant ABA receptors are also found in humans and further studies in this area could reveal important implications for people with cellular stress disorders.”
The lead authors of the current Science study are Fen-Fen Soon, Ley-Moy Ng, and Edward Zhou. The project was carried out in conjunction and collaboration with scientists from the National University of Singapore, Purdue University, The Scripps Research Institute, Scripps Florida, Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, the Synchrotron Research Center of Northwestern University, and University of California at Riverside.

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