QB3 Postdoc Seminar

Seminar | April 6 | 4:30-5:30 p.m. | 177 Stanley Hall

 QB3 - California Institute for Quantitative Biosciences

Speaker: Ellen Goodall (Andreas Martin lab)

Asymmetry in the 26S proteasome motor drives global conformational changes

The eukaryotic 26S proteasome is a complex molecular machine and is responsible for the bulk of targeted protein degradation in the cell. Substrates marked with ubiquitin are recognized by the proteasome regulatory particle before being unfolded and threaded into an interior core peptidase chamber, and previous cryo-EM studies of the proteasome have established a number of conformational states of the proteasome regulatory particle. Here we explore the allosteric network connecting the ATPase activity of the proteasome’s heterohexameric, AAA+-type ATPase to the larger structural rearrangements that occur during degradation of a substrate. Mutations preventing ATP hydrolysis in two of the six subunits specifically disrupts the ability of the proteasome to degrade substrates by decoupling conformational changes in the complex from substrate threading. Similarly, mutations introduced to disrupt a key contact between the ATPase motor and the rest of the regulatory particle also decouples substrate recognition from substrate degradation. Together these biochemical data give mechanistic insight into the sequence of conformational changes the proteasome undergoes during degradation of a substrate.

Speaker: Joseph Chen (Sanjay Kumar lab)

Mechanistic examination of glioblastoma cancer stem cell invasiveness

Glioblastoma is one of the most aggressive human cancers characterized by highly invasive cells that rapidly infiltrate the surrounding normal brain tissue. The disruption of tumor cell motility represents a promising therapeutic strategy to reduce invasive potential and improve outcomes; however, the specific mechanisms regulating aggressive motility of glioblastoma cells are not well understood. In our study, we focus on studying invasiveness by examining actin-based mutations as well as cell-cell junctional changes during glioblastoma progression. For actin portion of this study, we look at members of the LIM kinase (LIMK) family, LIMK1 and LIMK2, which are important modulators of actin polymerization and depolymerization, essential cellular mechanisms associated with cell polarization, migration, and invasion. Importantly, LIMK1/2 is overexpressed in many aggressive cancers including glioblastoma. With respect to junctional changes, we investigate the role of the mesenchymal cadherin, cadherin-11, in modulating cell invasion and survival. We provide evidence that these key proteins play important roles in modulating glioblastoma cancer stem cell invasion and tumorigenicity.