March 2001

From Yale University

Protein regulation study at Yale confirms suspicions on how hereditary blindness occurs

New Haven, Conn. -- A Yale research team, in collaboration with scientists at the Baylor College of Medicine, have studied signal transduction-the communication system developed by cells-to further understand how hereditary blindness occurs.

"Our results serve as a basis for understanding mutations that cause hereditary blindness and as a platform for drug development aimed at vision defects," said Kevin Slep, first author on the study he conducted while at Yale's Department of Molecular Biophysics and Biochemistry. "Our model system for studying signal transduction is the photo transduction cascade which occurs in the retina."

Slep said the system is involved in transmitting light energy. When the eye receives light energy, it has to transfer this energy into a biological signal and relay it to the brain. The eye does this by using a cascade of signal transduction proteins.

It has been known for some time that a visual protein called transducin activates a downstream protein called phosphodiesterase in the signal transduction pathway. But it wasn't clear how this activation occurred. The team eventually found that a third protein called RGS9 was interacting with transducin. This study, published in a recent issue of Nature takes a look at the interaction of all three proteins at the molecular level using x-ray crystallography.

The results not only reveal how transducin activates phosphodiesterase, Slep said, but in turn, how phosphodiesterase and RGS9 act in concert to inactivate transducin. This type of interaction is known as the negative feedback loop. "This is an amazing feature of the visual system," Slep said. "If transducin were allowed to continuously activate phosphodiesterase, all anyone would see is bright light, even if they were in a dark room.

The system had to develop a way in which transducin could be effectively turned off as soon as it activated phosphodiesterase, and not before. It wasn't until we solved the high resolution structure of all three proteins in a single complex that we understood the mechanism of phosphodiesterase's activation and transducin's inactivation."

"Now that we've seen the structure of the protein complex, we understand why a number of hereditary mutations result in blindness," said Slep. "We also see how various mutations would prevent transducin from interacting with phosphodiesterase, thereby preventing transmission of the visual signal. Transducin, Slep said, is just one of many G-proteins in the human body. Some of these G-proteins control smell and responses to adrenaline. Transducin controls vision.

"Our system establishes a trend that has wider implications for G-protein signaling," said Slep, who is now at the University of California, San Francisco. "The late Dr. Paul Sigler, the primary investigator in whose lab the research took place, referred to this structure as the 'Holy Grail,' indicative not only of the biology the structure would explain, but also of how difficult the results would be to obtain."

Slep adds, "While the system we investigated is specific to vision, it is highly homologous to numerous signal transduction systems such as those involved in taste, smell and response to adrenaline. As such, our model helps explain signal transduction in other systems, not only vision."

Other researchers on the study included Michele Kercher and Paul Sigler of Yale; and Wei He, Christopher Cowan and Theodore Wensel of Baylor College of Medicine.

This article comes from Science Blog. Copyright 2004

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