- Cell cycle, mitosis, ubiquitin ligases, anaphase promoting complex
The overarching goal of my research program is to understand the system of inter- and intra-molecular interactions that dynamically regulate the catalytic mechanisms of enzymes to precisely time the events of the cell cycle. We employ a hybrid technological approach, including enzyme kinetics, mutagenesis, X-ray crystallography, NMR spectroscopy, and cryo-EM, to characterize these molecular machines. Our results provide mechanistic insight into the cell cycle that will influence the drug design of cancer therapeutics.
UBE2S stimulates APC/C-UBE2C activity via a positive allosteric feedback to increase the levels of its own substrate (primed substrates). Consequently, UBE2S can then elongate ubiquitin chains in Ub-substrates. Overall, this increases the efficiency of substrate ubiquitination and substrate targeting for proteasomal degradation. We hypothesize this interplay between APC/C, UBE2C, and UBE2S is one of the aspects that help during rapid cell cycle transitions. For example, at the beginning of mitosis the MCC suppresses APC/C activity until the spindle checkpoint is satisfied. During this suppressing effect, the binding site of UBE2S on the APC/C is still available. Once the spindle checkpoint is satisfied, UBE2S bound to the APC/C boosts APC/C-UBE2C activity, degradation of key main substrates occurs, chromosomal segregation occurs, and finally mitosis is completed (shown as the finish line). ~Animation by Alejandro R. Martinez Chacin. Martinez-Chacin RC et al. Ubiquitin chain-elongating enzyme UBE2S activates the RING E3 ligase APC/C for substrate priming. Nat Struct Mol Biol. 2020 Jun;27(6):550-560.