Team learns how some proteins are taken to the garbage

Investigators find potential target for anti-cancer drug development

SAN ANTONIO (Sept. 27, 2011) — Disposing of spoiled food in our homes is essential for good health. And, so it is with the cells in our bodies. A team from The University of Texas Health Science Center San Antonio discovered how one type of used-up protein is shuttled to the protein garbage disposer in our cells.

Imbalances in the disposal of “spoiled” proteins in our cells can lead to wide-ranging diseases, from cancers to neurodegenerative disorders.

“The specific pathway under investigation is also linked to normal processes such as muscular, neuronal and cardiac development,” said Hai Rao, Ph.D., associate professor of molecular medicine at the Health Science Center.

Dr. Rao is senior author of the study, published in an August issue of Proceedings of the National Academy of Sciences.

The discovery involves several proteins including ubiquitin, Rad23 and Cdc48. Ubiquitin (Ub) acts like a quality-control marker, which targets “spoiled” proteins for destruction in the garbage disposer (called the proteasome).

“In this paper we uncovered a protein-protein interaction involved in shuttling damaged proteins from the site of ubiquitin tagging to their final destination, the proteasome,” Dr. Rao said.

Cdc48 and Rad23 act like maids cleaning the kitchen. When it’s time, the Cdc48 protein releases Rad23, which then escorts the marked proteins to the proteasome.

It is one of the few findings to date showing how proteins flagged for destruction with Ub are delivered to the proteasome. Imbalances in this disposal — too much or too little — may lead to protein damage. “Because uncontrolled protein stability has been linked to cancers and neurodegeneration, we expect our studies to have important implications with respect to the treatment of both diseases,” Dr. Rao said.

Some existing drugs for multiple myeloma and other cancers act as proteasome inhibitors. “Because Rad23 regulates a subset of selective proteins for destruction, Rad23 is likely a better, more precise drug target than the entire proteasome,” Dr. Rao said.

The paper’s first author is Guem Hee Baek, Ph.D. Second author is Ikjin Kim, Ph.D. Both are colleagues of Dr. Rao in the Department of Molecular Medicine at the UT Health Science Center.

This work was supported by a grant from the National Institutes of Health, National Institute of General Medical Sciences, GM078085, to Hai Rao, Ph.D., principal investigator, and grants from the Welch Foundation, AQ-1747, and U.S. Department of Defense, W911NF-11-10466.

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