New Insight Into the Controls on a Go...(he calpastatin molecule attach to calpai...),Health

Date:11/19/2008

he calpastatin molecule attach to calpain in the inhibition process," said Green, the report's senior author. "However, there was no overall picture of calpastatin that revealed how it was so precise in its attachment and potent in its function."

To obtain that overall picture, St. Jude researchers used the analytical technique of X-ray crystallography, with help from nuclear magnetic resonance (NMR) spectroscopy. In this widely used method of determining protein structure, researchers first crystallize a protein to be studied. Then, they direct X-rays through the crystal and deduce the protein structure from the diffraction pattern of those X-rays. To overcome the crystallization bottleneck, a lengthy and unpredictable variable in X-ray crystallography, the investigators used NMR spectroscopy to tailor the perfect enzyme-inhibitor complex.

Tudor Moldoveanu, Ph.D., a postdoctoral fellow in Green's laboratory, performed X-ray structural analysis on such a protein crystal that consisted of a critical part of the calpastatin molecule attached to calpain. The structural picture obtained of the two proteins clutched together clearly revealed why calpastatin so specifically attaches to calpain.

"Calpain has multiple domains, and what we saw was that calpastatin wraps itself around pretty much every domain of calpain," said Moldoveanu, the report's first author. This attachment not only blocks the portion of the enzyme called the active site, where calpain performs its snipping function, but also covers regions away from that site. Such a broad molecular embrace guarantees that calpastatin will potently and rapidly shut down calpain's function, Moldoveanu said. This broad embrace also guarantees that calpastatin will precisely recognize only calpains, rather than mistakenly attach to other similar enzymes in the cell.

Furthermore, the researchers discovered how calpastatin evades being che
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SOURCE St. Jude Children's Research Hospital Copyright©2008 PR Newswire. All rights reserved

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