Navigation Links
A cellular housekeeper, and potential target of obesity drugs, caught in action
Date:8/2/2010

Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory have obtained the closest look yet of how a gargantuan molecular machine breaks down unwanted proteins in cells, a critical housekeeping chore that helps prevent diseases such as cancer.

They pieced together the molecular-scale changes the machine undergoes as it springs into action, ready to snip apart a protein.

Their work provides valuable clues as to how the molecular machine, a giant enzyme called tripeptidyl peptidase II, keeps cells tidy and disease free. It could also inform the development of obesity-fighting drugs. A closely related enzyme in the brain can cause people to feel hungry even after they eat a hearty meal.

"We can now better understand how this very important enzyme carries out its work, which has not been described at a molecular scale until now," says Bing Jap, a biophysicist in Berkeley Lab's Life Sciences Division. He led the research with scientists from the University of California at Berkeley and Germany's Max Planck Institute of Biochemistry.

The scientists report their research August 1 in an advance online publication of the journal Nature Structural & Molecular Biology.

Tripeptidyl peptidase II is found in all eukaryotic cells, which are cells that a have membrane-bound nucleus. Eukaryotic cells make up plants and animals. The enzyme's chief duty is to support the pathway that ensures that cells remain healthy and clutter free by breaking down proteins that are misfolded or have outlived their usefulness.

It's not always so helpful, however. A variation of the enzyme in the brain degrades a hormone that makes people feel satiated after a meal. When this hormone becomes unavailable, a person can eat and eat without feeling full, which can lead to obesity.

Tripeptidyl peptidase II is also the largest protein-degrading enzyme, or protease, in eukaryotic cells. It's more than 100 times larger than most other proteases.

Scientists don't know how this behemoth of an enzyme targets and degrades specific proteins but it's good that the enzyme is so selective. If it degraded every protein it comes across, the cell would quickly die.

"We want to know how it's regulated, how it selects proteins to degrade, and how it cuts them apart," says Jap.

To help answer these questions, his team determined the changes the molecular machine undergoes as it readies itself for action. Using x-ray crystallography, they obtained an atomic-scale resolution structure of the molecular machine in its inactive state. This work was conducted at Berkeley Lab's Advanced Light Source, a national user facility that generates intense x-rays to probe the fundamental properties of substances.

They also developed a lower-resolution, three-dimensional map of the molecular machine in its activated state, meaning it's poised to snip apart a protein. This structure was determined using cryo-electron microscopy.

They then merged these two structures together, one dormant and the other ready to pounce on a protein.

"When we dock these structures, we can begin to ascertain the changes the enzyme undergoes as it transitions from an inactive to an active state," says Peter Walian, a scientist in Berkeley Lab's Life Sciences Division who also contributed to the research.

This first molecular-scale vantage of the enzyme in action offers insights into how it works. For example, the scientists found that only very small proteins can fit in the chamber the enzyme uses to break down proteins.

"This sheds light on how the enzyme targets specific proteins," says Jap.

They also learned more about how the enzyme uses a molecular ruler to mince proteins into pieces that only span three residues.

"This work is yielding valuable clues as to how the giant enzyme carries out very fundamental biological processes, with more insights to come," says Jap. "The obesity-related hormone is one of many interesting targets of the protease. There are likely other proteins and peptides, yet to be discovered, that are processed by this protease."


'/>"/>

Contact: Dan Krotz
dakrotz@lbl.gov
510-486-4019
DOE/Lawrence Berkeley National Laboratory
Source:Eurekalert

Related biology news :

1. Origins of multicellularity: All in the family
2. Biologists identify a new clue into cellular aging
3. Researchers demystifying complex cellular communications hubs found in sensory neurons
4. Intracellular express -- why transport protein molecules have brakes
5. Cellular mechanical forces may initiate angiogenesis
6. Tel Aviv University President Co-authors Important Paper Unraveling the Effect of Spatial Organization on Intracellular Chemistry
7. Spying on a cellular director in the cutting room
8. Blocking cancer in its path: New cellular defect discovered
9. New microscopy technique offers close-up, real-time view of cellular phenomena
10. OHSU researchers discover cellular mechanism that protects against disease
11. Shifting cellular energy metabolism may help treat cardiovascular disease
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/22/2016)... , June 22, 2016  The American College of Medical ... Show Executive Magazine as one of the fastest-growing trade ... 25-27 at the Bellagio in Las Vegas ... highest percentage of growth in each of the following categories: ... companies and number of attendees. The 2015 ACMG Annual Meeting ...
(Date:6/16/2016)... , June 16, 2016 ... is expected to reach USD 1.83 billion by ... View Research, Inc. Technological proliferation and increasing demand ... are expected to drive the market growth. ... The development of advanced multimodal techniques ...
(Date:6/3/2016)... LONDON , June 3, 2016 /PRNewswire/ ... Transport Management) von Nepal ... ,Angebot und Lieferung hochsicherer geprägter Kennzeichen, einschließlich ... weltweit führend in der Produktion und Implementierung ... an der Ausschreibung im Januar teilgenommen, aber ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... ... June 27, 2016 , ... Cancer experts from Austria, ... could be a new and helpful biomarker for malignant pleural mesothelioma. Surviving Mesothelioma ... read it now. , Biomarkers are components in the blood, tissue or ...
(Date:6/27/2016)... , June 27, 2016  Liquid Biotech ... announced the funding of a Sponsored Research Agreement ... circulating tumor cells (CTCs) from cancer patients.  The ... in CTC levels correlate with clinical outcomes in ... These data will then be employed to support ...
(Date:6/24/2016)... ... June 24, 2016 , ... While the majority of commercial spectrophotometers and fluorometers ... the 6000i models are higher end machines that use the more unconventional z-dimension of ... beam from the bottom of the cuvette holder. , FireflySci has developed several ...
(Date:6/23/2016)... 2016   Boston Biomedical , an industry ... to target cancer stemness pathways, announced that its ... Drug Designation from the U.S. Food and Drug ... including gastroesophageal junction (GEJ) cancer. Napabucasin is an ... cancer stemness pathways by targeting STAT3, and is ...
Breaking Biology Technology: