Mechanism for faulty protein disposal identified

December 7th, 2007 - 6:43 pm ICT by admin  

Washington , Dec 7 (ANI): The findings of a study have shed light on a unique mechanism through which myeloma cells discard defective or excess proteins out of the cells protein factory. This, the researchers say, could help in developing new cancer treatments.

The study was led by Linda Hendershot, Ph.D., a member of the St. Jude Department of Genetics and Tumor Cell Biology.

Key cellular components that carry out protein disposal were identified by the researchers and this finding can further aid in explaining the mechanism of cancer drugs called proteasome inhibitors and how they interfere with this process.

This is an important discovery as the newly identified components of the protein disposal mechanism could be targets for novel cancer drugs designed to kill the cell by blocking this mechanism.

Myelomas are cancers of plasma cells, which are the activated form of B lymphocytesimmune system cells that respond to infection by temporarily producing a large amounts of proteins called antibodies that attack the target.

The rapidly multiplying cancer cells constantly produce large numbers of new antibodies, increasing the chance for errors in the production process, consequently resulting in the accumulation of defective proteins that should be degraded.

Proteasome inhibitors are currently being used to treat some types of cancer including multiple myelomas, although many aspects of this cellular process remain poorly understood. Our study sheds new light on how that process works. said Linda Hendershot

The researchers focused their investigation on special channels in the membrane of the cells protein factory, called retrotranslocons.

They also studied a small collection of molecules that discards defective proteins out of the factory through the retrotranslocon so that they can be delivered to the cells protein shredder, a structure called the proteasome.

The protein factory, also known as the endoplasmic reticulum, resembles an origami workshop: In the endoplasmic reticulum, molecules called chaperones help to fold up newly made proteins into the exact shape that enables that particular protein to perform its assigned task.

Proteins, that have been folded successfully, are transferred to the cell surface or into the blood stream where they do their job.

However, if there is a flaw in the folding or it does not occur, the endoplasmic reticulum throws out defective proteins through channels called retrotranslocons and put into the proteasome, where they get degraded.

This process, called endoplasmic reticulum-associated degradation, ensures that defective proteins are not gathered in the endoplasmic reticulum and destroys the cell by disrupting the vital process of protein folding.

Earlier research identified a channel through the endoplasmic reticulum for glycosylated proteins, or proteins tagged with sugar molecules. This channel depends on the detection of the sugar molecules in order to identify the proteins and send them to the proteasome.

However, there was no information about the disposal of non-glycosylated proteins (proteins with few or no sugar molecules attached).

The scientists found that this particular group of proteins departed the endoplasmic reticulum through a channel, quite similar to the one used for glycoproteins but that has different components.

The team focused the study on non-glycosylated proteins called light chains and heavy chains, which are the building blocks for antibodies made by plasma cells.

Plasma cells after turning cancerous multiply rapidly and continue to produce large amounts of antibodies, some of which are not folded properly.

These cells depend on endoplasmic reticulum-associated degradation to dispose of unwanted proteins before they clog up the endoplasmic reticulum and eventually kill the cells.

Initially, The St. Jude team demonstrated that defective light chain and heavy chain proteins in plasma cells are degraded by the proteasome after being ejected from the endoplasmic reticulum and tagged with molecules called ubiquitina standard way the cell flags an unwanted protein for destruction.

Then, the reserachers examined the menagerie of molecules collaborating to pull defective proteins out of the endoplasmic reticulum and hand it over to the proteasome.

Hendershots team showed earlier that one of those molecules, a chaperone called BiP, initially helps newly made proteins undergo folding.

If this operation of folding fails, however, BiP becomes a conspirator with another member of the menagerie, called Herp, in order to send the defective protein to the proteasome.

Based on a series of detailed biochemical studies, it was demonstrated that Herp binds to both the ubiquitinated protein and the proteasome, apparently serving as a bridge to direct the protein to the shredder.

In addition to BiP and Herp, three other members of the menagerie, Derlin-1, p97 and Hrd 1 collaborate with Herp to pull out defective proteins from the retrotranslocon so that Herp can hand it over to the proteasome.

A report on this work appeared in one of the issues of Molecular Cell. (ANI)

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