Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New insight into the controls on a go-to enzyme

24.11.2008
St. Jude scientists report basic findings on critical enzyme’s regulation may hold key to understanding how to better treat an array of disorders

Scientists at St. Jude Children's Research Hospital have gained new insights into regulation of one of the body's enzyme workhorses called calpains.

As the cell's molecular overachievers, calpains function in many cellular processes, including the movement of cells in tissues, the death of damaged cells, insulin secretion, and brain cell and muscle function.

The downside of this broad set of responsibilities is that defective or overactive calpains have been linked to an array of disorders, including a form of muscular dystrophy, Type 2 diabetes, gastric cancers, Alzheimer's and Parkinson's diseases, cataracts, and the death of both heart muscle in heart attacks and of brain tissue in stroke and traumatic brain injury.

"Our basic findings on calpain regulation could add useful pieces to the puzzles of these disorders and perhaps reveal targets for drugs to treat them," said Douglas Green, Ph.D., chair of the St. Jude Department of Immunology.

Calpains are triggered by calcium flowing into the cell. This process induces the enzyme to snip apart many target proteins, as part of the cell's regulatory machinery. However, such a critical enzyme needs ultra-precise control, which is the job of another protein called calpastatin. A central question has been how calpastatin is so exquisitely specific in attaching to calpain and inhibiting it—essentially ignoring other highly similar enzymes in the cell.

In an article published in the November 20, 2008, issue of the journal Nature, Green and his colleagues report new information on the specificity of calpastatin.

"Previous studies on calpastatin had revealed how a few of the parts of the 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 chewed up by calpain. Calpastatin's survival enables it to be repeatedly recycled to inhibit calpain, making it an even more effective regulator.

The researchers' structural information also showed how calpain changes its shape once it is activated by calcium and how this transformation renders it a target of calpastatin attachment and thus inhibition.

"This new structural information on calpastatin and on calpain's conformational changes not only explains a lot about calpain's regulation," Green said. "It also gives us information we can use to develop targets for drugs that could either activate or inhibit calpain."

Summer Freeman | EurekAlert!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Enduring cold temperatures alters fat cell epigenetics
19.04.2018 | University of Tokyo

nachricht Full of hot air and proud of it
18.04.2018 | University of Pittsburgh

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

Im Focus: The Future of Ultrafast Solid-State Physics

In an article that appears in the journal “Review of Modern Physics”, researchers at the Laboratory for Attosecond Physics (LAP) assess the current state of the field of ultrafast physics and consider its implications for future technologies.

Physicists can now control light in both time and space with hitherto unimagined precision. This is particularly true for the ability to generate ultrashort...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Diamond-like carbon is formed differently to what was believed -- machine learning enables development of new model

19.04.2018 | Materials Sciences

Electromagnetic wizardry: Wireless power transfer enhanced by backward signal

19.04.2018 | Physics and Astronomy

Ultrafast electron oscillation and dephasing monitored by attosecond light source

19.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>