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St. Jude finds mechanism for faulty protein disposal
Date:12/6/2007

culum and eventually kill the cells.

The class of cancer drugs called proteasome inhibitors block endoplasmic reticulum-associated degradation as well as the destruction of proteins from other parts of the cells and cause defective proteins to overload this system, she said. We want to fully understand how endoplasmic reticulum-associated degradation works for antibodies made by plasma cells, so we can design more specific ways to block this process in myelomas.

The St. Jude team first 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.

The researchers then examined the menagerie of molecules that collaborate to pull defective proteins out of the endoplasmic reticulum and hand it over to the proteasome. Hendershots team showed previously that one of those molecules, a chaperone called BiP, initially helps newly made proteins undergo folding. If the folding operation fails, however, BiP becomes a conspirator with Herp, another member of the menagerie, to send the defective protein to the proteasome. Based on a series of detailed biochemical studies, the team showed 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 extract defective proteins from the retrotranslocon so Herp can hand it over to the proteasome.

Our study shows for the first time the role Herp plays at the retrotranslocon, said Yuki Okuda-Shimizu, Ph.D. a postdoctoral fellow in Hendershots laboratory who contributed significantly to the project. The study also describes how non-glycosylated proteins are removed from the endoplasmic ret
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Contact: Summer Freeman
summer.freeman@stjude.org
901-495-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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