Institute for Systems Biology Researchers Leverage Proteomics Technologies to Identify New Structures and Associations within Cells
New Strategies May Provide Insights into Human Disease

SEATTLE - Monday, December 20, 2004 - One of the major goals of proteomics research is to understand the associations that proteins make within cells that enable them to perform their various functions. Historically, this has been done one protein at a time. But now, researchers at the Institute for Systems Biology (ISB) have combined the classic principles in subcellular biochemistry established by Nobel Laureate Christian de Duve with modern proteomics technologies to perform the analysis on a global scale.

The research, published in the December 20th issue of The Journal of Cell Biology, outlined two complementary experiments utilizing isotope-coded affinity tags (ICAT) and tandem mass spectrometry to quantify the relative enrichment of proteins during the purification of peroxisomes. This allowed scientists to distinguish those proteins that partition with peroxisomes from contaminating proteins and develop a catalogue of candidate proteins that occupy the peroxisome in the yeast Saccharomyces cerevisiae.

Peroxisomes, which are intracellular organelles and contain more than 50 enzymes involved in diverse biochemical processes, were chosen as a test-bed for the idea because they are relatively poorly characterized, play a central role in human metabolism and are linked to a number of human health concerns including aging, cancer, heart disease, obesity, diabetes, and neurological disorders. In addition, a number of rare genetic diseases are caused by peroxisomal dysfunction.

A first step to better understand the molecular networks underlying the biochemistry, biogenesis and dynamic responses of organelles necessitates a complete catalogue of the proteins associated with each cellular compartment and an understanding of their individual and collective functions. Understanding peroxisome biology at the molecular level and how peroxisomes communicate with the rest of the cell will help to develop both treatments and methodologies to treat disease.

Lead investigator, Dr. Marcello Marelli, a post doctoral fellow in Dr. John Aitchison's laboratory at the Institute for Systems Biology said that in this study, several proteins not previously shown to localize with peroxisomes, were found to associate with, or function in, diverse aspects of peroxisome biology. Importantly, the study also revealed that proteins are borrowed from other cellular structures and recruited to the organelle during its development.

Further characterization of the components identified in the study promise to illuminate diverse aspects of peroxisome biology and the regulatory processes that control not only the origins of "newborn" peroxisomes, their turn-over (destruction of peroxisomes), and the mechanisms that monitor and govern the birth and maturation of these versatile organelles, but also may shed light on how organelles, in general, are regulated and assembled.

"This new approach will enable us to interrogate existing subcellular structures and establish their content, but also enable us to identify novel structures that may have been overlooked by more standard approaches," stated Dr. Aitchison.

Yeast has several advantages that make it an ideal model organism for studying human peroxisomal disorders. First, and most importantly, the mechanism of peroxisome function and development are similar between yeast and humans. Many genes necessary for peroxisome biogenesis, whose mutations affect human health, were first described in yeast. Thus, the understanding of the biology of yeast peroxisomes will lead to understanding human disease. Furthermore, yeast is a simple genetically tractable organism for which many molecular biology and computational tools for a systems biology approach have been developed, many of which are simply not yet possible in humans.

About the Institute for Systems Biology
The Institute for Systems Biology (ISB) is an internationally renowned non-profit research institute dedicated to the study and application of systems biology. ISB's goal is to unravel the mysteries of human biology and identify strategies for predicting and preventing diseases such as cancer, diabetes and AIDS. The driving force behind the innovative "systems" approach is the integration of biology, computation, and technology. This approach allows scientists to analyze all of the elements in a system rather than one gene or protein at a time. Located in Seattle, Washington, the Institute has grown to seven faculty and more than 170 staff members; an annual budget of more than $25 million; and an extensive network of academic and industrial partners. For more information about the ISB or the Human Proteome Folding Project, visit: www.systemsbiology.org