An atomic-resolution view of an enzyme found only in the eye has given researchers at the University of Washington (UW) clues about how this enzyme, essential to vision, is activated. The enzyme, phosphodiesterase 6 (PDE6), is central to the way light entering the retina is converted into a cascade of signals to the brain.
This particular form of the enzyme comes from the cone photoreceptors of the retina and has not been well-researched, in contrast to its rod form. Rods are involved in night vision and motion sensation; the cones are responsible for color sensitivity, visual acuity, daylight vision, and adjustment to bright light.
The section of the enzyme molecule that most interests the researchers is the so-called GAF A domain. A small messenger molecule, cGMP, binds to the GAF A domain to regulate the enzyme.
"The domain binds to this small molecule with extremely high sensitivity," said UW biochemist Clemens Heikaus, who along with Sergio E. Martinez, now a research associate at Rutgers, carried out the study. "From our structure, we can infer why it prefers cGMP over other messenger molecules." He added that the domain is quick in recognizing and responding to the messenger molecule to create an instantaneous flow of information to the brain.
Using X-ray crystallography and nuclear magnetic resonance, the researchers discovered that the enzyme undergoes major structural changes upon binding of the cGMP molecule.
Before binding occurs, the GAF domain is like an outstretched palm with the fingers wiggling, Heikaus said. After the cGMP molecule binds, the GAF domain closes and becomes less dynamic. In this state it looks more like a closed fist.
Further analysis of the consequences of this conformational change may lead to a better understanding of how the photoreceptor PDE helps regulate the path of signals that enable us to see, as well as provide general information on proteins with GAF domains.
"The addition of a simple, small molecule to the GAF domain affects the entire PDE enzyme," Heikaus said. Researchers think the binding to the domain may act as a switch that turns on the enzyme.
The research findings were published in the Sept. 19 Journal of Biological Chemistry. The article was selected as a Paper of the Week. The journal cover featured a striking image of the iris of Heikaus' eye, photographed by UW ophthalmology imaging supervisor Brad Clifton. Superimposed in the center of the pupil was a three-dimensional structure of the GAF domain.
In humans, GAF-containing proteins are rare. In plants and bacteria, GAF domains are widespread and are specialized for binding a variety of molecules. Some of these plant and bacteria GAF domains are important in detecting light, but they do so through a mechanism that is completely different from vision in vertebrate animals.
GAF domains emerged more than 3 billion years ago in early forms of life, and remained as animals and humans evolved, a phenomenon evolutionary biologists call conservation. Human GAF domains have similar protein folds, and a similar way of binding signal-triggering molecules inside a "pocket," as do GAF domains in more primitive creatures.
Humans have only a few kinds of GAF domains, all of which are in enzymes within the PDE family. They perform important functions not only in vision but also in hearts, lungs, and blood vessels. PDE5, an enzyme closely related to PDE6, is the therapeutic target for sildenafil, known by the trade name Viagra. In some men, this drug also inhibits PDE6 in the eyes, causing a temporary change in color vision.
More knowledge of the basic mechanisms of PDEs in vision may lead someday to better drug treatment for loss of eyesight from damaged retinas, such as occurs in night blindness and retinitis pigmentosa.
Leila Gray | EurekAlert!
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
Pollen taxi for bacteria
18.07.2018 | Technische Universität München
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
18.07.2018 | Life Sciences
18.07.2018 | Materials Sciences
18.07.2018 | Health and Medicine