[PAST EVENT] Applied Science and Biology Seminar
LocationISC3 (Integrated Science Center), Room 2280
540 Landrum Dr
Williamsburg, VA 23185Map this location
Access & Features
- Open to the public
Title of Talk: "Ste24p: A Membrane-Bound Protease with Novel Structure, Provocative Mechanism and Emergent Biology."
Michael C. Wiener, Ph.D., Professor
Department of Molecular Physiology and Biological Physics
University of Virginia
Abstract: The integral membrane protein protease Ste24p, a zinc metalloprotease, was initially discovered and characterized via yeast genetics by its role in mating and maturation of the a-factor mating pheromone. Human Ste24p (ZMPSTE24) processes prelamin A, a component of the nuclear lamina; mutations in ZMPSTE24 that diminish its activity give rise to genetic diseases of accelerated aging (progerias). Additionally, lipodystrophy, acquired from the standard highly active antiretroviral therapy (HAART) used to treat AIDS patients, likely results from off-target interactions of HIV (aspartyl) protease inhibitor drugs with ZMPSTE24. The structure of Ste24p (Pryor et al., Science 339:1600 ) possesses a novel membrane protein fold, consisting of seven long kinked transmembrane helices that surround a membrane-bound ~14,000 ?3 ?reaction chamber? containing the zinc metalloprotease active site, and a ?processive processing? model has been proposed for its function. Ste24p has generally been consigned to be a ?CaaX protease? component of a multi-enzyme pathway mediating isoprenylation, proteolytic processing, and methylation of protein substrates for increased membrane-binding affinity. However, a recent series of papers, including work from our lab, provides significant evidence for broader biological function. Ste24p is a key factor in several endoplasmic reticulum (ER) processes, including the unfolded protein response, a cellular stress response of the ER, and removal of misfolded proteins from the translocon. Also, in collaboration with Prof. Walter Schmidt (University of Georgia), we demonstrated that substrate prenylation is dispensable for cleavage by Ste24p (Hildebrandt et al., JBC 291:14185 ). I will present an overview of recent advances in the study of this fascinating enzyme, with an emphasis on recent unpublished results from our laboratory. These results include: dependence of enzyme kinetics upon substrate environment (membrane-bound vs. soluble), effects of absolutely conserved residues upon function and protein stability, and emergence of an important non-proteolytic function for Ste24p. This work was supported by the US National Institutes of Health [R01GM108612].