Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Surprise! Cells have second source of phosphate

20.12.2004


New source means new cellular communication



For 50 years, thousands of labs around the world have studied cells’ critical internal communications, and scientists had assumed the speakers were known. But now, in the Dec. 17 issue of Science, Johns Hopkins researchers report finding not just a new participant, but a brand new conversation that has implications for treating disease and understanding biology.

Much of cells’ internal communication revolves around two very important words -- "stop" and "go" -- elicited when a small bit, called phosphate, is added onto proteins. This addition turns protein activities up or down and fine tunes cells’ responses to what’s happening outside their borders. This communication can go awry in diseases, including cancer, and be corrected by various drugs.


The source of these phosphate bits has been known -- a molecule called adenosine triphosphate, or ATP. But in their new report, the Johns Hopkins scientists describe a brand new source of phosphate that seems to work with as many proteins as targeted by ATP, but in a completely different way.

"There are already drugs that affect particular roles of ATP to treat cancer and other conditions, so we envision drugs that increase or decrease specific activities of this new source of phosphate could be important in neurologic and psychiatric illnesses, and perhaps in cancer as well," says Solomon Snyder, M.D., professor and director of neuroscience, one of the departments in Johns Hopkins’ Institute for Basic Biomedical Sciences.

"Nobody in a million years would have thought there was another way for cells to add phosphate groups to proteins other than using ATP," he adds. "Addition of phosphates to proteins -- phosphorylation -- is the most fundamental signaling mechanism in all life, and the new source of phosphate represents a very different kind of process than the one we’ve known about. It represents a totally new form of cellular communication."

Unlike ATP, the new phosphate source, known as inositol pyrophosphate (IP7), modifies proteins without any help, just binding directly to the protein and leaving behind one of its phosphates, the researchers report. Their early evidence also suggests IP7 might be most important in regulating the release of chemicals in the brain and in controlling the cellular machinery that builds proteins.

While IP7’s newly found role is likely to surprise many, Snyder has been expecting it. In the early 1990s, he noticed the first reports that IP7 and a related molecule called IP8 existed, interesting to him because for 15 years, he’d been studying related inositol (pronounced in-AH-si-tahl) phosphates.

But unlike the molecules he’d been working with, which look like bracelets with three to six phosphate "charms," IP7 and IP8 had too many phosphates to fit on the bracelet. Instead, the seventh and eighth phosphates would have to be linked to another phosphate "charm" rather than to the "bracelet" itself.

"ATP has a similar phosphate-phosphate connection, so I speculated that IP7 and IP8 might also be able to give up that extra phosphate," says Snyder, who is also a professor of pharmacology and molecular sciences and of psychiatry. "Proving it turned out to be very difficult technically."

First, it took several years for then-graduate student Susan Voglmaier to isolate an enzyme that builds IP7 (from IP6), an advance the team published in 1996. It took a few more years for postdoctoral fellow Adolfo Saiardi, Ph.D., to clone the three enzymes that make IP7 and to use them to make IP7 in which the extra phosphate was radioactive.

After finally making sufficient quantities of radioactive IP7, Saiardi and postdoctoral fellow Rashna Bhandari, Ph.D., mixed it with a "puree" of mouse brain or kidney, which produced hundreds of radioactive proteins. After numerous experiments to rule out other possibilities, the researchers could finally conclude that IP7 gives away its extra phosphate to proteins.

"We think IP7 phosphorylation of proteins is as universal as ATP phosphorylation," says Snyder, whose lab is continuing to study IP7’s protein targets and where on proteins its phosphates are added. "The enzymes that build IP7 are most prevalent in the brain, but they are found everywhere. What we’ve learned so far is just the tip of the iceberg."

Already, Bhandari has discovered that two of the proteins most heavily phosphorylated by IP7 are involved in the ribosome, the cellular machine that reads genetic instructions and constructs proteins. IP7 also controls the cellular "mail room" -- the preparation and release of tiny packages that contain messengers, such as neurotransmitters in the brain that create movement, memory and mania.

The researchers also have shown in work described in the Journal of Biological Chemistry, online now, that proper activity of one of the enzymes that makes IP7 is critical in cell death -- because of IP7’s role in modifying proteins.

"So drugs that activate the enzyme and stimulate production of IP7 would increase cell death, which is what one wants to do in cancer treatment," says Snyder. "Drugs inhibiting the enzyme would prevent cell death, the goal in treating stroke and neurodegenerative diseases."

The first proof of how ATP works was the impetus for the 1992 Nobel Prize in Physiology or Medicine. During the mid-1950s, the awardees, Americans Edmond Fischer and Edwin Krebs, isolated the first example of an enzyme that takes ATP’s phosphate and gives it to a protein, and showed that the phosphate changes the protein’s function.

Since then, scientists have found and studied thousands of other ATP-controlled proteins. While IP7 also controls protein activity, its role in cellular communication -- coordinating internal activities to respond to external events -- is likely quite distinct from ATP’s, given the differences Snyder and his colleagues have already observed. IP7 may even add its phosphate to phosphates already on proteins, which, if confirmed, is completely unheard of, says Snyder.

Authors are Saiardi, Bhandari, Snyder, Adam Resnick and Adele Snowman, all of Hopkins. Saiardi is now at University College London. The research was funded by the National Institute of Mental Health and the National Institute on Drug Abuse.

Joanna Downer | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>