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Research Interests
We are using biochemical, cell biological, genetic, and molecular approaches in conjunction with the yeast system to better understand the function of several proteases that act on isoprenylated proteins. Examples of isoprenylated proteins include the Ras family of oncoproteins, Ras-related proteins, kinases, and secreted fungal mating pheromones, among many others. Understanding the function of these proteases may lead to novel therapeutic strategies for cancer, Alzheimer's disease, and other diseases.
Rce1p is an ER membrane-localized protease of unknown mechanism. This protease is essential for the maturation of isoprenylated molecules that are involved in cellular transformation (e.g., Ras and RhoB). We aim to define the proteolytic mechanism of Rce1p and to develop pharmacological inhibitors that have anti-tumor potential. Rce1p has partial overlapping function with the ER membrane-localized, zinc-dependent Ste24p protease, which has been linked to premature aging (progeria) because of its role in the processing of lamin A. Thus, we are also trying to understand the functional differences of Rce1p and Ste24p to better understand their relative physiological importance.
Ste23p and Axl1p are zinc-dependent metalloproteases that are required for the maturation of the isoprenylated yeast a-factor mating pheromone. These proteases are part of the M16 family of metalloproteases, which includes the insulin-degrading enzyme that has a proposed protective function in Alzheimer's disease (AD). Our research on Ste23p and Axl1p is designed is to gain a better understanding of these largely uncharacterized yeast proteases and the M16 metalloprotease family as a whole, thus potentially providing novel insight into new methods for the treatment of AD.
Selected Recent Publications
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Manandhar SP and Schmidt WK
Small molecule Rce1p CaaX protease inhibitors.
Submitted.
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Porter SB, Hildebrandt ER, Breevoort SR, Dore TM, and Schmidt WK
Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones.
Biochim Biophys Acta (2007), in press.
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Alper BJ, Nienow TE, and Schmidt WK
A common genetic system for functional studies of Ptr and related M16A proteases.
Biochem J (2006), 398(1):145-52.
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Plummer LJ, Hildebrandt ER, Porter SB, Rogers VA, McCracken J, Schmidt WK
Mutational analysis of the ras converting enzyme reveals a requirement for glutamate and histidine residues.
J Biol Chem (2006), 281(8):4596-605.
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Kim S, Lapham AN, Freedman CG, Reed TL, Schmidt WK
Yeast as a tractable genetic system for functional studies of the insulin-degrading enzyme.
J Biol Chem (2005), 280(30):27481-90.
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