Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Disorderly protein brings order to cell division

30.01.2007
St. Jude study shows disorderliness of the p27 yoke that suppresses activity of the cell-division molecule CDK2 is key to the ability of p27 to participate in its own destruction and set CDK2 free

The secret to the ability of a molecule critical for cell division to throw off the protein yoke that restrains its activity is the yoke itself—a disorderly molecule that seems to have a mind of its own, say investigators at St. Jude Children's Research Hospital, Innsbruck Medical University (Austria) and Max Planck Institute (Martinsried, Germany).

The researchers showed that the disorderly protein yoke, called p27, participates in its own destruction by swinging the end of its long arm up into a key side pocket of the cell division molecule called CDK2. After the end of p27 slips into the pocket, CDK2 marks p27 for destruction by tagging it with a molecule called phosphate. The tag signals the cell's protein destruction machinery to dispose of p27, freeing CDK2 to trigger cell division.

The finding is important because it explains how CDK2 normally shrugs off p27. Once free of p27, CDK2 can participate in a specific step of cell division. The findings also explain how some abnormal enzymes cause this to occur prematurely, putting cell division into overdrive—a state that produces cancer. A report on the work appears in the January 25 issue of the journal Cell.

... more about:
»CDK2 »Kinase »Kriwacki »T187 »abnormal »activity »amino acid »elbow »enzymes »p27 »yoke

The long p27 molecule drapes itself like an arm over the shoulders and down the side of CDK2, the researchers explained. The upper arm of p27 binds tightly to the shoulders of CDK2; as the arm drops over the shoulders, the "elbow" of p27 inserts itself into a side "pocket" of the molecule.

Meanwhile, the long, floppy forearm and hand of p27 hangs freely below CDK2. Initailly, this is where the story of p27 became puzzling: the part of p27 that CDK2 must tag is on the "hand" at the free end of the floppy arm, at a point called amino acid threonine 187 (T187). But CDK2 can tag T187 only when this part of p27 fits into the pocket of CDK2, where the elbow of p27 is already lodged.

"Previous studies produced conflicting evidence to explain how CDK2 disposes of p27," said Richard Kriwacki, Ph.D., associate member of the Department of Structural Biology at St. Jude. "We knew p27 inactivated CDK2; yet we also knew that CDK2 tags T187 with phosphate even while it still carries the p27 yoke on its shoulders. The question was, how does the pocket of CDK2 tag T187 while T187 is so far away and the pocket itself has the elbow of p27 jammed into it? What we knew about the process didn't make sense."

The key to both normal and premature tagging of p27 and its subsequent destruction is the activity of enzymes called kinases, according to Kriwacki. Kinases are enzymes that tag specific amino acids—the building blocks of proteins—with phosphate. CDK2 itself is a kinase, which is why it can tag the hand of p27 with a phosphate group.

The team showed that a specific type of kinase tags the elbow of p27 at a spot called amino acid Y88. This causes the elbow to change shape and pop out of CDK2's side pocket. The floppy end of p27 carrying T187 is then free to swing up and insert its hand into the pocket of CDK2, where T187 gets tagged by phosphate. "Our study showed that because the floppy part of p27 is so unstructured it can move around freely and swing up and into the CDK2 pocket," Kriwacki said.

Normally, p27 is removed from CDK2 only at a specific time during the precise process that leads to cell division, Kriwacki noted. "However, some abnormal kinase enzymes, called tyrosine kinases, jump the gun and tag the elbow of p27 before CDK2 should become active," he said. "This sets CDK2 free to push the cell to divide, even when it shouldn't."

"The findings explain why the anti-cancer drug Gleevec® is effective in treating some forms of leukemia in certain individuals," said Yuefeng Wang, Ph.D., a postdoctoral student in Kriwacki's laboratory who did much of the work on this project. "Gleevec blocks the abnormal tyrosine kinase BCR-ABL and prevents it from tagging Y88," he said. "That keeps the elbow of p27 lodged in the pocket of CDK2 and prevents premature cell division. Our study suggests that other cancer-causing tyrosine kinases may also trigger premature CDK2 activity."

Results of the study suggest that blocking the CDK2 pocket after an abnormal kinase dislodges the p27 elbow might be an effective strategy for preventing cancer cell division, Kriwacki said.

Summer Freeman | EurekAlert!
Further information:
http://www.stjude.org
http://www.stjude.org/media/0,2561,453_2816_21701,00.html

Further reports about: CDK2 Kinase Kriwacki T187 abnormal activity amino acid elbow enzymes p27 yoke

More articles from Life Sciences:

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

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...

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

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>