Seminar by Guillermo Montoya

Speaker: Guillermo Montoya, The Novo Nordisk Foundation Center for Protein Research
Host: Kresten Lindorff-Larsen, Biomolecular Sciences

Abstract
Cellular growth and division are regulated by an integrated protein network that ensures the genomic integrity of all eukaryotic cells during mitosis. Microtubules play an important role in several cellular processes, particularly in the formation of the mitotic spindle. The regulation of microtubule dynamics during mitosis is key for spindle formation. Spindle defects, arising from failures in setting up the microtubules, lead to chromosomal instability and aneuploidy; a common cause of tumour development. One of the most effective strategies for cancer treatment so far has been to interfere with the highly dynamic mitotic spindle microtubules; tubulin remains the most successful spindle targeted molecule in cancer. To date, novel anti-mitotic agents have demonstrated limited efficacy in clinical trials and classical anti microtubule drugs are still considered the best approach for cancer therapy. We are attempting to dissect the molecular working mechanism of CCT/TRiC the molecule responsible for the folding of tubulin and actin, the essential building blocks of the cytoskeleton. This molecular machine is essential for sister chromatid separation through the folding of key anaphase promoting factor subunits, such as Cdc20. Using a hybrid approach we are aiming to dissect the molecular recognition of these key substrates by the chaperoning. After solving the structure of this macromolecular machine at 5.5 Å in complex with tubulin, one of its main substrates, we have proposed a mechanism for this molecular machine. This mechanism involves several protein regions. Our future aim is to get high resolution information regarding the atomic structure and to disect the regulation of this protein complex using site-directed mutagenesis.