Navigation Links
'Reaper' protein strikes at mitochondria to kill cells
Date:10/20/2010

Our cells live ever on the verge of suicide, requiring the close attention of a team of molecules to prevent the cells from pulling the trigger. This self-destructive tendency can be a very good thing, as when dangerous precancerous cells are permitted to kill themselves, but it can also go horribly wrong, destroying brain cells that store memories, for instance. Rockefeller University scientists are parsing this perilous arrangement in ever finer detail in hopes that understanding the basic mechanisms of programmed cell death, or apoptosis, will enable them eventually to manipulate the process to kill the cells we want to kill and protect the ones we don't.

In experiments published last month in the Journal of Cell Biology, researchers led by postdoctoral associate Cristinel Sandu in Hermann Steller's Strang Laboratory of Apoptosis and Cancer Biology drilled down on a protein aptly named Reaper, which was first described in a 1994 paper by Steller in Science. Under the right conditions,

Reaper interferes with molecules called inhibitor of apoptosis proteins (IAPs), which prevent the cell from irrevocably initiating its autodestruct sequence. By inhibiting these inhibitors, Reaper essentially takes the brakes off the process of apoptosis, pronouncing a cell's death sentence. Other molecules called caspases then carry that sentence out.

"Like the grim reaper, Reaper is an announcer of death, but not the executioner," says Steller, who is also a Howard Hughes Medical Institute investigator. "It's like the key that starts the engine."

Reaper and the other Drosophila IAP antagonists Hid and Grim are known to trigger apoptosis in flies, and related proteins serve a similar function in humans and other mammals. But exactly how and where Reaper initiates apoptosis has not been well understood. Sandu and colleagues bred genetically modified strains of flies that expressed variations on the Reaper protein specifically in flies' eyes. This allowed them to assess the contribution of individual protein motifs to Reaper's apoptosis inducing powers, and what they found was that a particular helical domain was crucial for the formation of Reaper complexes, and could be modified to be even more powerful than the regular protein. The more deadly Reaper variants were obvious by the damage caused to the flies' eyes.

In a series of biochemical experiments, the researchers also found that Reaper must travel to the mitochondria, the cell's energy factories, to effectively deliver its death sentence, and that to get there, it must hitch a ride on the Hid protein, with which it interacts. By tagging Hid and Reaper fluorescently, Sandu could visualize Hid and Reaper acting in a complex and gathering at the membrane of the mitochondria. When Reaper was engineered to go directly to the mitochondrial membrane, it resulted in a molecule that is far superior at triggering cell death than regular Reaper. Further experiments suggested that in a complex with Hid, Reaper is protected from degradation as the cells began to die.

"So now we have Hid and Reaper working very closely together," Sandu says. "And the localization to the mitochondria is crucial to the initiation of apoptosis." Drugs that mimic a small part of the function of Reaper are already in clinical trials. The discovery of a way to make Reaper a much better killer, namely by targeting it directly to the mitochondria, provides new avenues to explore for improving cancer therapies. "Adding this element that takes Reaper directly to the mitochondria is not something people would have thought of before this," Steller says.


'/>"/>

Contact: Brett Norman
bnorman@rockefeller.edu
212-327-7613
Rockefeller University
Source:Eurekalert

Related biology news :

1. New clues to how cancer-related proteins plasmin, thrombin lose inhibition
2. UMMS researchers identify protein associated with sporadic ALS
3. Key difference in how TB bacteria degrade doomed proteins
4. Shifting forms: Penn study shows how variations of same protein affect immune response
5. New look at multitalented protein sheds light on mysteries of HIV
6. Pitt team finds protein that sets the stage for exchanges of DNA code in eggs and sperm
7. Novel protein critical for cellular proliferation discovered
8. Model unfolds proteins gently
9. Protein provides link between calcium signaling in excitable and non-excitable cells
10. Slicing proteins with Occams Razor
11. NIH awards Rutgers $47.5 million to advance groundbreaking research on protein structures
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/23/2017)... , Mar. 23, 2017 Research and ... System Market Analysis & Trends - Industry Forecast to 2025" ... ... grow at a CAGR of around 8.8% over the next decade ... industry report analyzes the market estimates and forecasts for all the ...
(Date:3/22/2017)... Calif. , March 21, 2017 ... analytics company serving law enforcement agencies, announced today the ... as director of public safety business development. ... diversified law enforcement experience, including a focus on the ... In his most recent position, Mr. Sheridan served as ...
(Date:3/16/2017)... HANOVER, Germany , March 16, 2017 CeBIT 2017 - Against ... Continue Reading ... Used combined in one project, multi-biometric solutions ... ... Identification Systems) ...
Breaking Biology News(10 mins):
(Date:4/20/2017)... CALIFORNIA (PRWEB) , ... April 20, 2017 , ... ... firm for the life sciences and healthcare industries, is pleased to announce Holger ... new established USDM subsidiary “USDM Europe GmbH” based in Germany. , Braemer is ...
(Date:4/20/2017)... April 20, 2017 /PRNewswire/ - Prometic Life Sciences Inc. (TSX: PLI) ... at the International Liver Congress ("ILC") 2017 of the European ... Amsterdam on the positive effects of PBI-4050 ... of obesity and metabolic syndrome. ... According to Dr. Lyne Gagnon, Vice-President of R&D Pre-clinical ...
(Date:4/20/2017)... ... April 20, 2017 , ... ... unique intellectual property (IP) sharing and commercialization model. , The Center for Advancing ... main component of this effort is bringing the IP to the attention of ...
(Date:4/20/2017)... 2017 For today, Stock-Callers.com redirects investors, ... development and clinical research aimed at treating diseases and medical ... Keryx Biopharmaceuticals Inc. (NASDAQ: KERX), Kite Pharma Inc. (NASDAQ: KITE), ... can access our complimentary research reports on these stocks now ... http://stock-callers.com/registration ...
Breaking Biology Technology: