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    Quest to understand APC identifies small protein’s key stabilizing role

    Brenda Shulman

    Four years after Brenda Schulman, PhD, Structural Biology and Genetics and Tumor Cell Biology, set out to explore the universe within the APC, her team recently sent back its first dispatch from the frontier.

    APC, short for anaphase promoting complex, is to cell division what mission control is to a space shuttle flight. While the role of mission control is well understood, 15 years after APC was identified as a master regulator of mitosis and cell division, investigators are still working to understand exactly how the enzyme is assembled and functions.

    The September edition of Nature Structural & Molecular Biology includes the first answers from Schulman’s laboratory.

    Researchers hope a better understanding of the APC will lead to new strategies for blocking uncontrolled cell division, a hallmark of cancer. Scientists have already found APC mutations in cancer cells, said Jing Wang, PhD, a postdoctoral fellow in Schulman’s laboratory and the paper’s lead author.

    APC is a highly specialized member of a family of enzymes known as E3 ligases. It is also one of the largest. E3 ligases regulate cell behavior by turning certain proteins off at critical junctures. They work by tagging those proteins for destruction with a special regulatory protein known as ubiquitin. In the case of APC, the process controls a cell’s entrance into and exit from mitosis and much of cell division.

    This report focuses on one of the smallest of APC’s more than one dozen subunits. Investigators report the small rod-shaped protein, known as CDC26, helps stabilize the larger complex by serving as a lynchpin for another protein essential to keeping APC together. The publication includes the first crystal structure of any protein-protein interaction in APC.

    “Our work reveals how CDC26, which is one of the smallest proteins in the APC, accomplishes the critical task of helping hold this huge complex together,” explained Billy Dye, PhD, a research specialist in Schulman’s laboratory and a co-author of this study. CDC26 was known to be a small heat shock protein; on that basis, scientists inferred that CDC26 imparted stability. But the targets of CDC26’s stabilizing function were previously unknown.

    Schulman, Wang, Dye and their colleagues found that CDC26 helps stabilize the structure of APC6, another component of the large APC complex. Earlier work established that APC6 is essential for proper assembly of the APC molecule. Thus, the stabilizing effect of CDC26 is critical to APC function and the control of cell division. Prior to this work, CDC26’s genetic makeup provided no clues about its structure or function.

    For Schulman, the report is just the beginning. Some of her attention is now turned to the larger questions of how APC is assembled and functions. Schulman is a Howard Hughes Medical Institute (HHMI) investigator and the paper’s senior author. She said the findings suggest that like APC6, certain other APC components may become more stable when bound to a peptide-like piece of protein. Several APC subunits include a helical structure called a tetratricopeptide (TPR) motif, which investigators suspect might also prove important for APC assembly.

    Being named a HHMI in 2005 meant Schulman could embrace the challenge of deciphering APC. “Hughes gave me the resources to take on the project and recruit who I needed to tackle it. I needed to find rigorous scientists who were sufficiently adventurous and who believed the project would work,” she explained.

    Along with using crystallography to determine the structure of the CDC26-APC6 complex, investigators used biochemistry and yeast genetics to determine its function. Working in budding yeast, they also examined a role for CDC6 stabilization of APC6 in cell division.

    As further evidence of the importance of the CDC26-APC6 coupling, the researchers found the association at work in species as evolutionarily distant as yeast and humans. In fact, the scientists reported that in some species human CDC26 could serve as a stand-in for the species’ own.

    The research was supported in part by the National Institutes of Health, HHMI and ALSAC.

    October 2009