UCSD Researchers Determine Mechanism For Degradation of G Proteins

Researchers at the University of California, San Diego (UCSD) School of Medicine have identified a previously unknown component of the body’s cellular garbage disposal called the ubiquitin system, which is responsible for regulation of cell function by removal of abnormal and unneeded proteins.

Published in the July 8, 2003 issue of Proceedings of the National Academy of Sciences, the study provides the first description of a molecule called GAIP interacting protein N terminus (GIPN) that plays a key role in the degradation of G proteins, which are switches that turn activities on or off in the cell.

Senior author Marilyn Farquhar, Ph.D., a UCSD professor and chair of the Department of Cellular and Molecular Medicine, noted the findings should be of interest to the pharmaceutical industry since G proteins regulate everything from hormone secretion to the beating of the heart.

The researchers found that GIPN appears to specifically target G proteins for degradation and thereby regulates G protein signaling by controlling the amount of G protein expressed in the cell. This occurs via GIPN binding to the N terminus of G alpha interacting proteins (GAIP), which is the mechanism that sets the ubiquitin system in motion.

The ubiquitin system is used extensively by the cell for the turnover and degradation of proteins in both the cytoplasm, the material surrounding the nucleus, and in cell membranes. Ubiquitin, itself, is a small peptide tag that marks a protein for destruction. The interaction of GIPN and GAIP, which was also discovered by the UCSD team, is part of the machinery that places the little ubiquitin tag on a protein.

A source of study by numerous research labs, the ubiquitin system is crucial for nearly every significant activity in the cell. Although this system of protein turnover was first identified in the 1930s, the molecular mechanisms responsible for the process have remained largely unknown.

Ubiquitin-mediated degradation of proteins plays an important role in the control of numerous processes, such as the way in which extracellular materials are incorporated into a cell, the movement of biochemical signals from the cell membrane, and the regulation of cellular functions such as transcriptional on-off switches. The ubiquitin system has been implicated in the immune response and development. Abnormalities in the system are known to cause pathological conditions, including malignant transformation.

“As usual with scientific projects like this one, you have to go much more into the details of the mechanism,” Farquhar said. “We have a number of experiments now underway to firm up the precise mechanism.”

“Discovery is finding something new—in this case, a new protein; then, it takes a long time to work out the biology,” she added.

The co-first authors of the PNAS paper are Thierry Fischer, Ph.D., an assistant project scientist in Farquhar’s laboratory, and Luc De Vries, Ph.D., a former UCSD post-doctoral student who currently works at the Institut de Recherche Pierre Fabre CRPF, Castres Cedex, France. An additional contributor to the study is Timo Meerloo, B.S., a UCSD research specialist.

The study was funded by the National Institutes of Health.