Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps research scientists elevate little-studied cellular mechanism to potential drug target

12.12.2011
For years, science has generally considered the phosphorylation of proteins -- the insertion of a phosphorous group into a protein that turns it on or off -- as perhaps the factor regulating a range of cellular processes from cell metabolism to programmed cell death.

Now, scientists from the Florida campus of The Scripps Research Institute have identified the importance of a novel protein-regulating mechanism -- called sulfenylation -- that is similar to phosphorylation and may, in fact, open up opportunities to develop new types of drugs for diseases such as cancer.

The study was published December 11, 2011, in an advance online edition of the journal Nature Chemical Biology.

"With this paper, we've elevated protein sulfenylation from a marker of oxidative stress to a bona fide reversible post translational modification that plays a key regulatory role during cell signaling," said Kate Carroll, a Scripps Research associate professor who led the study. "The sulfenyl modification is the new kid on the block."

During periods of cellular stress, caused by factors such as exposure to UV radiation or chronic disease states like cancer, the level of highly reactive oxygen-containing molecules can increase, resulting in inappropriate modification of proteins and cell damage. In sulfenylation, one oxidant, hydrogen peroxide, functions as a messenger that can activate cell proliferation through oxidation of cysteine residues in signaling proteins, producing sulfenic acid. Cysteine, an amino acid (natural protein building block), is highly oxidant sensitive.

Conventional wisdom has long held that if hydrogen peroxide does exist in the cell at any appreciable level, it represents a disease state, not a regulatory event. The new study shows that sulfenylation is actually a positive protein modification, and that it's required for signaling through the pathway, a validation of a long-held belief in some scientific circles that hydrogen peroxide functions as a general signaling molecule, not an oxidative "bad boy" to be eliminated at all costs.

A New Chemical Probe

To explore the process, Carroll and her colleagues developed a highly selective chemical probe -- known as DYn-2 -- with the ability to detect minute differences in sulfenylation rates within the cell.

With the new probe, the team was able to show that a key signaling protein, epidermal growth factor receptor (EGFR), is directly modified by hydrogen peroxide at a critical active site cysteine, stimulating its tyrosine kinase activity.

The technology described in the new paper is unique, Carroll said, because it allows scientists to trap and detect these modifications in situ, without interfering with the redox balance of the cell. "Probing cysteine oxidation in a cell lysate is like looking for a needle in a haystack," she said, "our new approach preserves labile sulfenyl modifications and avoids protein oxidation artifacts that arise during cell homogenization."

As with phosphorylation, future studies on sulfenylation will delve into the exciting discovery of new enzymes, new signaling processes, and new mechanisms of regulation.

Another broad impact of these findings, Carroll said, is to open up an entirely new mechanism to exploit for the development of therapeutics, particularly in cancer. "It should influence the design of inhibitors that target oxidant-sensitive cysteine residues in the future," she said.

The first author of the study, "Peroxide-dependent Sulfenylation of the EGFR Catalytic Site Enhances Kinase Activity," is Candice E. Paulsen of the University of Michigan. Other authors include Thu H. Truong and Stephen E. Leonard of the University of Michigan; and Francisco J. Garcia, Arne Homann and Vinayak Gupta of Scripps Research.

The study was supported by the Camille Henry Dreyfus Teacher Scholar Award and the American Heart Association.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neuroscience, and vaccine development, as well as for its insights into autoimmune, cardiovascular, and infectious disease. Headquartered in La Jolla, California, the institute also includes a campus in Jupiter, Florida, where scientists focus on drug discovery and technology development in addition to basic biomedical science. Scripps Research currently employs about 3,000 scientists, staff, postdoctoral fellows, and graduate students on its two campuses. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, is ranked among the top ten such programs in the nation.

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Exciting Plant Vacuoles
14.06.2019 | Julius-Maximilians-Universität Würzburg

nachricht A microscopic topographic map of cellular function
13.06.2019 | University of Missouri-Columbia

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: MPSD team discovers light-induced ferroelectricity in strontium titanate

Light can be used not only to measure materials’ properties, but also to change them. Especially interesting are those cases in which the function of a material can be modified, such as its ability to conduct electricity or to store information in its magnetic state. A team led by Andrea Cavalleri from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg used terahertz frequency light pulses to transform a non-ferroelectric material into a ferroelectric one.

Ferroelectricity is a state in which the constituent lattice “looks” in one specific direction, forming a macroscopic electrical polarisation. The ability to...

Im Focus: Determining the Earth’s gravity field more accurately than ever before

Researchers at TU Graz calculate the most accurate gravity field determination of the Earth using 1.16 billion satellite measurements. This yields valuable knowledge for climate research.

The Earth’s gravity fluctuates from place to place. Geodesists use this phenomenon to observe geodynamic and climatological processes. Using...

Im Focus: Tube anemone has the largest animal mitochondrial genome ever sequenced

Discovery by Brazilian and US researchers could change the classification of two species, which appear more akin to jellyfish than was thought.

The tube anemone Isarachnanthus nocturnus is only 15 cm long but has the largest mitochondrial genome of any animal sequenced to date, with 80,923 base pairs....

Im Focus: Tiny light box opens new doors into the nanoworld

Researchers at Chalmers University of Technology, Sweden, have discovered a completely new way of capturing, amplifying and linking light to matter at the nanolevel. Using a tiny box, built from stacked atomically thin material, they have succeeded in creating a type of feedback loop in which light and matter become one. The discovery, which was recently published in Nature Nanotechnology, opens up new possibilities in the world of nanophotonics.

Photonics is concerned with various means of using light. Fibre-optic communication is an example of photonics, as is the technology behind photodetectors and...

Im Focus: Cost-effective and individualized advanced electronic packaging in small batches now available

Fraunhofer IZM is joining the EUROPRACTICE IC Service platform. Together, the partners are making fan-out wafer level packaging (FOWLP) for electronic devices available and affordable even in small batches – and thus of interest to research institutes, universities, and SMEs. Costs can be significantly reduced by up to ten customers implementing individual fan-out wafer level packaging for their ICs or other components on a multi-project wafer. The target group includes any organization that does not produce in large quantities, but requires prototypes.

Research always means trying things out and daring to do new things. Research institutes, universities, and SMEs do not produce in large batches, but rather...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

 
Latest News

Concert of magnetic moments

14.06.2019 | Information Technology

Materials informatics reveals new class of super-hard alloys

14.06.2019 | Materials Sciences

New imaging modality targets cholesterol in arterial plaque

14.06.2019 | Medical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>