Key protein interactions involved in neurodegenerative disease revealed

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have defined the molecular structure of an enzyme as it interacts with several proteins involved in outcomes that can influence neurodegenerative disease and insulin resistance. The enzymes in question, which play a critical role in nerve cell (neuron) survival, are among the most prized targets for drugs to treat brain disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

The study was published online ahead of print on November 8, 2012, by the journal .

The new study reveals the structure of a class of enzymes called c-jun-N-terminal kinases (JNK) when bound to three peptides from different protein families; JNK is an important contributor to stress-induced apoptosis (cell death), and several studies in animal models have shown that JNK inhibition protects against neurodegeneration.

"Our findings have long-range implications for ," said TSRI Professor Philip LoGrasso, who, along with TSRI Associate Professor Kendall Nettles, led the study. "Knowing the structure of JNK bound to these proteins will allow us to make novel substrate competitive inhibitors for this enzyme with even greater specificity and hopefully less toxicity."

The scientists used what they called structure class analysis, looking at groups of structures, which revealed subtle differences not apparent looking at them individually.

"From a structural point of view, these different proteins appear to be very similar, but the biochemistry shows that the results of their binding to JNK were very different," he said.

LoGrasso and his colleagues were responsible for creating and solving the crystal structures of the three peptides (JIP1, SAB, and ATF-2) with JNK3 using a technique called x-ray crystallography, while Nettles handled much of the data analysis.

All three peptides have important effects, LoGrasso said, inducing two distinct inhibitory mechanisms—one where the peptide caused the activation loop to bind directly in the ATP pocket, and another with allosteric control (that is, using a location on the protein other than the active site). Because JNK signaling needs to be tightly controlled, even small changes in it can alter a cell's fate.

"Solving the crystal structures of these three bound peptides gives us a clearer idea of how we can block each of these mechanisms related to cell death and survival," LoGrasso said. "You have to know their structure to know how to deal with them."

More information: "Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases," December 5, 2012 print edition of Structure.

Related Stories

Scientists find way to block stress-related cell death

Jun 02, 2011

Scientists from the Florida campus of The Scripps Research Institute have uncovered a potentially important new therapeutic target that could prevent stress-related cell death, a characteristic of neurodegenerative diseases ...

New role for the JNK protein

Jul 14, 2010

Put simply, a tumor is the result of out-of-control cell growth. To assure that the cell cycle - the cell's process of duplicating itself to make more cells - goes smoothly, a large network of proteins tells other proteins ...

Signaling to chromatin

Jan 03, 2012

(Medical Xpress) -- Scientists from the Friedrich Miescher Institute for Biomedical Research (FMI) in collaboration with their colleagues from the Department of Biosystems Science and Engineering of the ETH ...

Recommended for you

Growing a blood vessel in a week

Oct 24, 2014

The technology for creating new tissues from stem cells has taken a giant leap forward. Three tablespoons of blood are all that is needed to grow a brand new blood vessel in just seven days. This is shown ...

Testing time for stem cells

Oct 24, 2014

DefiniGEN is one of the first commercial opportunities to arise from Cambridge's expertise in stem cell research. Here, we look at some of the fundamental research that enables it to supply liver and pancreatic ...

Team finds key signaling pathway in cause of preeclampsia

Oct 23, 2014

A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause ...

Rapid test to diagnose severe sepsis

Oct 23, 2014

A new test, developed by University of British Columbia researchers, could help physicians predict within an hour if a patient will develop severe sepsis so they can begin treatment immediately.

User comments