Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps research scientists identify new regulatory mechanism for critical protein signaling domain

10.04.2007
Unexpected findings offer insight into T cell development, possible therapies for immune disorders

The study is being published in Science Express, an advanced online edition of the journal Science, on April 5. It will appear in the print version of Science later this spring.

In findings the authors called "unexpected and striking," the study found that a new regulating messenger IP4, a small soluble molecule, augments the binding of three different PH domain proteins to one of the most commonly recognized membrane lipids, PIP3. The study also showed that inhibiting production of IP4 can result in reduced protein binding to membranes and reduced activation of key signaling molecules in developing T cells, leading to a block of T cell maturation and to severe immunodeficiency in animal models.

"This study changes how we think about the T cell receptor signaling process and a well established general signaling mechanism, protein recruitment to membranes through PH domains," said Karsten Sauer, a Scripps Research scientist who led the study. "For the first time, we have clearly established a new way through which the PH domain can be positively regulated in vivo-IP4 augments the binding of PIP3 to these domains. In fact, it resembles PIP3. Until our study, the widely accepted idea was that recruitment of PIP3 binding PH domains to the membrane was primarily regulated by the supply and turnover of PIP3. The second completely new finding is that PH domain proteins can form aggregates through their PH domains. PH domain aggregation may enhance the membrane binding process."

Sauer suggests models for how IP4 might augment the binding of PIP3. In one, IP4 binds to a PH domain, changing its structure to one with a high affinity for IP4 and PIP3, a process commonly known as the "induced fit" model. In the second model, the PH domain pre-exists as an aggregate; IP4 binding to one subunit forces changes in the other subunit(s) so that they bind PIP3 with greater ease. This process is commonly known as an allosteric or cooperative mechanism.

Sauer offers a helpful analogy for the newly uncovered mechanism: "IP4 acts very like a clever engineer. If you were trying to dock your ship at a space station but found that the docking stations weren't fully compatible, the station would send over an engineer called IP4 and he would reconfigure your dock to fit the space station."

Repercussions for T Cell Development

Signaling from T cell receptors triggers the generation of PIP3 and IP4, Sauer explained, leading to the recruitment of proteins to the cell membrane from the cytosol, the internal part of the cell. This receptor signal is part of the mechanisms by which T cells, key players of the immune system, protect us against attack by pathogens such as viruses. However, defective T cell development can lead to a number of immune diseases including allergies like asthma and autoimmune diseases like rheumatoid arthritis, while severely reduced T cell development or function can lead to immunodeficiency diseases such as AIDS.

Using a mouse mutant lacking ItpkB, the enzyme that produces IP4, Sauer and his colleagues showed that without the enzyme, T cells could not develop to maturity.

Because T cell development is regulated by receptor signaling, Sauer said, if the T cell doesn't signal properly, it is normally killed through programmed cell death or other mechanisms. In immature T cells-called double positive cells-if the signal is correct, the cells undergo positive selection in the thymus and are allowed to develop into mature CD4 or CD8 single positive (SP) T cells. Damaged or nonfunctional cells are eliminated.

"IP4 is generated after T cell receptor stimulation," he said. "We found that if IP4 cannot be made due to lack of ItpkB, important signaling molecules including the protein tyrosine kinase Itk can not be properly recruited to the cell membrane. Itk is a key activator of another enzyme, PLC g1, in T- cells. PLC g1 is important for signaling in many cells, because it generates the secondary messenger molecules IP3 and DAG (diacylglycerol). We found that ItpkB deficient double positive cells have reduced PLCg1 activity and cannot make normal amounts of DAG. Without the IP4 or DAG messengers, which are essential for positive selection of T cells, these ItpkB-deficient T cells cannot develop into mature, functional cells."

Positive selection of T cells is disrupted by this lack of IP4 and DAG in the mutant mice, the study noted. Quite remarkably, the authors could rescue several aspects of positive selection by treating ItpkB deficient cells with a DAG analog, PMA. DAG is well known for helping to mediate T cell receptor signaling by activating the Ras/Erk pathway, a key signal pathway whose misregulation is often involved in cancer. It is still too early to tell if IP4 plays a broader role in Ras regulation in other cells, Sauer said.

"This is something we stumbled into-the possibility of regulating the Ras pathway with IP4 at the level of DAG production through PLCg1," he said. "In the immature, double positive T cells, this circuitry is essential for positive selection. If you prevent IP4 production, you can never get positive selection-unless you provide a DAG analog like PMA-and that is a very provocative discovery."

Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Studies and Analyses:

nachricht New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)

nachricht Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

Researchers invent process to make sustainable rubber, plastics

25.04.2017 | Materials Sciences

Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017

25.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>