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Chemistry Weekly Seminar - Dr. Martin St. Maurice

Posted on 2018-02-14 in Events
Apr 27, 2018



Title: A swing and a miss. Allostery and carrier domain movements in pyruvate carboxylase

Abstract: Pyruvate carboxylase (PC) is a multi-functional biotin-dependent enzyme that catalyzes the ATP-dependent carboxylation of pyruvate to oxaloacetate. The reaction occurs in two separate catalytic domains, coupled by the long-range translocation of a biotinylated carrier domain (BCCP) over ~70 Å.  We used a series of hybrid PC enzymes to explore the range of catalytically productive translocation pathways for the BCCP domain. Contrary to the current model, structural and kinetic studies reveal that the BCCP domain of PC adopts multiple translocation pathways during catalysis. Furthermore, the allosteric activator, acetyl CoA, promotes one specific intermolecular carrier domain translocation pathway over all the others. These results are inconsistent with long-standing interpretations of induced conformational changes during PC-catalyzed turnover. Instead, multiple direct observations of BCCP domain positioning reveal that the carrier domain samples multiple conformations in a dynamic equilibrium. Given the similarities with increasingly well-characterized multifunctional carrier domain proteins involved in the modular synthesis of natural products, the factors influencing carrier domain movement and regulation in PC are likely to be broadly applicable to a wide range of enzyme systems.

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