The array offers scientists a cutting edge research tool allowing them to analyze the specificities of glycan binding proteins (GBP's), which function through their binding to such sugar chains.

1 Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Denmark

2 Institute of Human Genetics, University of Aarhus, Denmark

3 Department of Biological Sciences and BioX Program, Stanford University, CA, USA

4 Department of Cardiology, Aarhus University Hospital, Denmark

S. Vang, Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby Sygehus, Brendstrupgaardsvej, DK-8200 Ã…rhus N, Denmark Fax: +45 89496018 Tel: +45 89495150 E-mail: vang@ki.au.dk

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common hereditary cardiac conditions. Both are frequent causes of sudden death and are often associated with an adverse disease course. Alpha-cardiac actin is one of the disease genes where different missense mutations have been found to cause either HCM or DCM. We have tested the hypothesis that the protein-folding pathway plays a role in disease development for two actin variants associated with DCM and six associated with HCM. Based on a cell-free coupled translation assay the actin variants could be graded by their tendency to associate with the chaperonin TCP-1 ring complex/chaperonin containing TCP-1 (TRiC/CCT) as well as their propensity to acquire their native conformation

“This is a unique signaling pathway,� says Randal Kaufman, Ph.D., a professor of biological chemistry in the U-M Medical School and an HHMI investigator. “In most pathways, there are multiple components and crosstalk. But there’s only one IRE1 gene and one protein that carries out a unique biochemical reaction. This makes IRE1 a perfect target for pharmacological intervention for B cell-driven autoimmune diseases, like myasthenia gravis or systemic lupus erythematosus.�

Results from the study will be published in the Feb. 1 issue of the Journal of Clinical Investigation.

Kaufman studies fundamental signaling pathways involved in the production of new proteins in the cell’s endoplasmic reticulum (ER). The process begins with chains of amino acids, which are deposited in the ER membrane in response to coded instructions from genes. Chaperone proteins fold these amino acid chains into specific shapes and direct them to different areas of the ER for processing.

The disease, called GM1 gangliosidosis, disrupts the normal function of brain cells and causes them to self-destruct. The St. Jude discovery offers strong evidence for the cause of GM1 gangliosidosis in children. GM1 gangliosidosis is a lysosomal storage disorders, an inherited disease in which one or more enzymes in the lysosomes are defective. Lysosomes are the cell's recycling centers, where proteins, fats and other molecules are broken down into their basic building blocks, which are then reused to make new molecules.

Lysosomal storage diseases occur when lysosomes lack the enzymes they need to perform their recycling tasks, leading to abnormal accumulation of the molecules the lysosome is supposed to break down. These diseases are responsible for most severe cases of nerve degeneration and mental retardation among children.

Using lasers to initiate and probe the folding process, a group including chemist Timothy Zwier have precisely determined the energies needed to twist tryptamine, a molecule with several flexible "hinges" that bears a close resemblance to an amino acid, the basis of proteins. Understanding the energy pathways that these molecules take passing from one conformation to another could provide new understanding of the elusive process of protein folding - an essential part of the development of these fundamental biological molecules. And though tryptamine forms only a tiny portion of a protein, a better understanding of this close chemical relative to serotonin and melatonin could provide insights into these other substances' effect on the brain.

"If you want to know how molecules function in the body, you can't just look at their structure - you have to look at the dynamics of how they change," said Zwier, who is a professor of chemistry in Purdue's School of Science. "On a small scale, we have found a way to look at the dynamic processes that makes one such molecule change shape. While we're still a long way from understanding how proteins take on their complex shapes, this work could be a step in that direction."

"FamClash is quite successful at qualitatively predicting the pattern of the specific activity of the hybrids," the researchers report in this week’s online issue of the Proceedings of the National Academy of Sciences. "By identifying incompatible residue pairs in the hybrids, this method provides valuable insights for protein engineering interventions to remedy these clashes," the researchers say.

FamClash is a computer method used to predict which hybrid enzymes are likely to have activity and which are not. Hybrid enzymes form when researchers combine similar enzymes from two or more different organisms. The variant enzymes are broken and recombined with parts from the original enzymes creating the new one.

Prions (pronounced PREE-ons) are one of countless types of proteins found in normal cells, and are at the center of the mystery. Scientists, who identify proteins by their shapes and molecular structures, know the job descriptions of many of them: Some act like bricks in the structure of a cell, while others help cells carry out chemical reactions or communicate with other cells. Prions appear to be important since there are so many of them in our brain cells, but, like the boss' son-in-law, their role in the whole organization is unclear.

In fact, one British researcher found that genetically modified mice without prions look and act exactly the same as other mice. "You can't talk to a mouse, and maybe it's lacking in some function, but as far as (the researcher) could tell, the mouse was perfectly normal," said David Eisenberg, who studies prions at the University of California at Los Angeles.

As proteins form within cells, their long chains of amino acids fold up like fiendishly intricate origami. Since the 1930s, scientists have known that a protein's folded shape is key to its function, making it possible for hemoglobin to carry oxygen or for collagen to bind together skin. But figuring out how and why proteins fold the way they do has become one of the great, enduring challenges in biochemistry.

It's easy for proteins to get corrupted while folding in the crowded confines of a cell, and misfolded proteins can cause all sorts of trouble.

When the abnormal form comes into contact with normal transporter prions, the normal ones begin a chain-reaction of bizarre folding that ultimately leads to the destruction of neurologic tissue and death.

All proteins are simple chains of amino acids that coil into specific shapes to perform their biological function.

In the folding process, proteins are assisted by molecular chaperones that function to prevent misfolding or, in the case of already misfolded proteins, to detect them and prevent their accumulation.

Faulty proteins have been implicated in such neurodegenerative diseases as Huntington's, Parkinson's and Alzheimer's.

Morimoto and colleagues have shown that elevated levels of molecular chaperones promote longevity.

The researchers focused on a master protein called heat shock factor.