Protein 97 Synapse-associated (SAP97)

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Researchers Reveal Secret of Key Protein in Brain and Heart Function

Synapse-associated protein 97The model shows the PDZ domain of the SAP97 protein in a ribbon format, highlighting its structural elements. The intra-cellular portion of the NMDA receptor is shown as ball-and-stick format atoms. SAP97 is a scaffolding protein, facilitating nerve signals.

Brown University researchers have solved the structure of a critical piece of SAP97, a protein used to keep hearts beating and brains learning. Results, reported by Dale Mierke in The Journal of Biological Chemistry, put science a step closer to understanding how this protein aids in brain and heart function.

PROVIDENCE, R.I. — Brown University biologists have solved the structure of a critical piece of synapse-associated protein 97 (SAP97) found in abundance in the heart and head, where it is believed to play a role in everything from cardiac contractions to memory creation. Results are published in The Journal of Biological Chemistry.

Dale Mierke, associate professor of medical science at Brown, said that knowing how a piece of SAP97 is built is an important step. Now that part of the protein’s structure is solved, scientists can create a molecule to disable it. That, in turn, will allow them to fully understand SAP97’s role in the body. And that will point drug makers to targets for developing new ways to treat cardiac or neurological diseases.

“To arrive at a solution, you need to understand the problem,” Mierke said. “Solving protein structures opens doors for effective treatments.”

SAP97 is found mainly in the central nervous system and is known as a “scaffolding” protein. In this role, it serves as a sort of tether, grabbing proteins inside the cell critical to nerve signaling and keeping them close to N-methyl-D-asparate (NMDA) receptors at the cell surface. NMDA receptors help usher in a neurotransmitter called glutamate that is essential for learning and memory and also plays a role in drug addiction. A similar scaffolding mechanism is at work in the heart, where it affects basic functions, including the heartbeat.

SAP97 is a complex protein made up of five “domains” similar to a train comprised of an engine and four boxcars. In their experiments, Mierke, graduate student Lei Wang and postdoctoral research fellow Andrea Piserchio – all colleagues in the Department of Molecular Pharmacology, Physiology and Biotechnology – focused on the engine. This domain, known as PDZ1, is where the protein links to NMDA receptors. The team used high-resolution nuclear magnetic resonance spectroscopy to solve the structure of PDZ1, as well as a small portion of the receptor to which it binds.

Mierke said the group is now developing a molecule that can inhibit PDZ1 as well as PDZ2, the first boxcar on the multi-domain protein.

The National Institutes of Health funded the work.

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cosmic string warps the space-time around it.

Is it a cosmic string we're seeing?

THE case for the existence of cosmic strings has just been boosted. If confirmed, these one-dimensional threads of energy that can span millions of light years could be the first sign of extra dimensions in the universe. Cosmic strings are predicted by string theory. They are gigantic counterparts of the strings that are thought to give rise to the fundamental particles of matter. String theory suggests that our universe may be a three-dimensional island, or "brane", and that the big bang was the result of a collision between our universe and another 3D brane. The collision would have given rise to one-dimensional cosmic strings, and finding such a string would strengthen the theory and support the idea that extra dimensions exist.

The immense energy of a cosmic string would warp the space-time around it. If one existed somewhere between us and a distant galaxy, say, the warped space-time would create two possible paths for the light from the galaxy to reach Earth. This would result in two identical images of the galaxy in our sky, just a whisker apart. Last year, that's exactly what Mikhail Sazhin of Capodimonte Astronomical Observatory in Naples, Italy, and the Sternberg Astronomical Institute in Moscow, Russia, and his colleagues found. They named the pair CSL-1 (New Scientist, 18 December 2004, p 30).

Many astronomers were sceptical of Sazhin's claim that a string was creating the images. Abraham Loeb of the Harvard-Smithsonian Center for Astrophysics in Cambridge, Massachusetts, said that CSL-1 is merely two very similar galaxies that happen to be close together. Now, Sazhin's team has presented more evidence that the two images are of the same galaxy. In March, the team used the European Southern Observatory's Very Large Telescope at Paranal, Chile, to record detailed spectra of the two galaxies and found that they are identical (www.arxiv.org/astro-ph/0506400 ). This adds further weight to the possibility that CSL-1 is an artefact of a string, he says. "We are 99.9 per cent sure of this."

Loeb remains unconvinced. "It is not clear whether the quality of the spectra is sufficient to separate, for example, the Milky Way galaxy from the Andromeda galaxy in the local group of galaxies," he says. "Both the Milky Way and Andromeda might have similar spectra." He adds that if the astronomers could use their technique to tell these neighbours apart, then it would make their case for CSL-1 much stronger. Sazhin believes his team's technique would be precise enough to distinguish the Milky Way from Andromeda, even if they were as far away as CSL-1, but admits more work needs to be done to demonstrate this.

If a string is producing the twin galaxy images, the edges of the images should be extremely sharp, but our turbulent atmosphere prevents telescopes on Earth from detecting this. Now Sazhin has been granted turbulence-free observation time on the Hubble Space Telescope. "The resolution of the HST will allow us to detect the specific signature produced by the cosmic string," he says. "We hope it will reduce the scepticism of other astronomers." ###

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