Dr. Walter K. Schmidt

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University of Georgia
College of Arts and Sciences
Biochemistry and Molecular Biology
Assistant ProfessorAppointed: 2001
Georgia Cancer Coalition
Professional Headshot of Walter K. Schmidt

Mailing Address

A414B Life Sciences
Dept. of Biochemistry and Molecular Biology
University of Georgia
Athens, Georgia 30602
United States

Contact Information

Phone: (706) 583-8241
Fax: (706) 542-1738
wschmidt@bmb.uga.edu
http://www.bmb.uga.edu/wschmidt

Qualifications

Ph.D., University of California, Berkeley, Molecular and Cell Biology, 1995.
B.A., Rice University, Biology and Biochemistry, 1989.

Expertise and Research Interests

My research expertise relates to membrane-localized proteases. These proteases are often essential components of cell signaling and disease pathways (e.g. Notch signaling during development, cholesterol regulation, the ER stress response, and beta-amyloid production associated with Alzheimer's disease). My research is focused on several membrane-localized proteases that are required for the biogenesis of prenylated signaling molecules, which are defined by the presence of a covalently attached lipid at the C-terminus. Examples of prenylated molecules include Ras, Ras-related proteins, the gamma-subunit of trimeric G-proteins, and secreted fungal mating pheromones. Because prenylated molecules function in a variety of cellular pathways that are linkedto human disease (e.g. Ras and cancer), understanding the function of the proteases required for the biogenesis of prenylated molecules may lead to novel therapeutic strategies for cancer and other diseases.

Other Expertise

Biochemistry
Metalloenzymes
Post-translational modification
Lipid modified proteins
Protein secretion

Future Research

We are using a multi-disciplinary approach that utilizes biochemistry, cell biology, proteomics and yeast genetics to better understand the function of proteases that act on isoprenylated proteins. Rce1p is a membrane-localized protease of unknown mechanism. This protease is essential for the biogenesis of isoprenylated molecules that are involved in cellular transformation (e.g. Ras and RhoB). Thus, a research goal is to define the proteolytic mechanism of Rce1p and to develop pharmacological inhibitors that have anti-tumor potential. Rce1p is one of two proteases known to cleave isoprenylated proteins, with the second being the membrane-localized, zinc-dependent Ste24p protease. These proteases have partially overlapping substrate specificity. Thus, weare also trying to understand the rules governing this specificity in the context of certain substrates. Axl1p and Ste23p are related, zinc-dependent metalloproteases that are likely to be membrane-associated. These proteases are part of the M16 family of metalloproteases, which also includes the mammalian protease insulysin. Axl1p is required for the maturation of the yeast a-factor mating pheromone, and it also has an undefined role in establishing bud site selection in haploid yeast. Ste23p has a limted role in pheromone production and no established role in bud site selection. The research on Axl1p and Ste23p is designed is to gain a better understanding of these largely uncharacterized proteases and the M16 metalloprotease family as a whole, which includes the insulin-degrading enzyme (IDE) that is proposed to have a protective role in Alzheimer's disease.

Industrial Relevance

Because prenylated molecules function in a variety of cellular pathways that are linked to human disease (e.g. Ras and cancer), understanding the function of the proteases required for the biogenesis of isoprenylated molecules may lead to novel therapeutic strategies for cancer and other diseases.

Keywords

COS Keywords:

Alzheimer's Disease, Anatomy, Biochemistry, Biochemistry, Proteins, Cell Biology, Molecular Biology.

Additional Terms:

Lipid-Modified Proteins, Membrane Proteins, Metalloenzyme Studies, Proteases, Protein Purification.

Languages

(Reading, Writing, Speaking)

English: (Fluent, Fluent, Fluent)
Spanish: (Fluent, Functional, Fluent)

Memberships

American Society for Microbiology
Society for Advancement of Chicanos and Native Americans in Science

Honors and Awards

2002-2002, Searle Scholar Nominee University of Georgia
2001-2006, Distinguished Cancer Clinician/Scientist Award, Georgia Cancer Coalition, University of Georgia, Cancer Research
2000-2000, Gordon Research Conference Award, Hormonal and Neural Peptide Processing Conference, Outstanding Research Presentation
1997-1999, Individual National Research Service Award., National Institutes of Health, Post-Doctoral Studies
1993-1993, Outstanding Graduate Student Instructor Award, University of California-Berkeley, Undergraduate Instruction
1990-1995, Pre-doctoral Fellowship Award, Howard Hughes Medical Institute, University of California-Berkeley, Graduate Studies
1989-1989, College Achievement Award, Jones College, Rice University, Community Service
1989-1990, UC Minority Fellowship Award, University of California, Graduate Studies
1985-1989, Briggs Memorial Scholar Award, Rice University, Undergraduate Studies
1985-1989, NHSF Scholar Award, National Hispanic Scholarship Foundation (NHSF), Rice University, Undergraduate Studies

Previous Positions

1999-1999, Part-time Faculty, Johns Hopkins University, Krieger School of Arts and Sciences, Part-time Graduate Program
1995-2001, Postdoctoral Fellow, Johns Hopkins University, School of Medicine, Cell Biology and Anatomy

Funding Received

  • Alzheimer's Drug Discovery Foundation: Enhancing IDE-mediated destruction of Abeta and other amyloidogenic peptides, $50,000, 2008 to 2009.
  • State of Georgia: GA Tech/UGA Biomedical Research Program, $50,000, 2006 to 2007.
  • State of Georgia: GA Tech/UGA Biomedical Research Program, $50,000, 2005 to 2006.
  • National Institutes of Health (NIH): R01 GM067092, $825,000, 2005 to 2010.
  • National Institutes of Health (NIH): R03 NS53625, $50,000, 2005 to 2006.
  • Georgia Research Alliance: Georgia Cancer Coalition Award, $300,000, 2001 to 2006.
  • National Institutes of Health (NIH): Individual National Research Service Award, $47,580, 1997 to 1999.

Publications

  • Manandhar SP, Hildebrandt ER, Schmidt WK (Oct 2007) Small-molecule inhibitors of the Rce1p CaaX protease., Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening, 12 (7), 983-93 Abstract
  • Porter SB, Hildebrandt ER, Breevoort SR, Mokry DZ, Dore TM, Schmidt WK (Jun 2007) Inhibition of the CaaX proteases Rce1p and Ste24p by peptidyl (acyloxy)methyl ketones., Biochimica et biophysica acta, 1773 (6), 853-62 Abstract
  • Alper BJ, Nienow TE, Schmidt WK (Aug 2006) A common genetic system for functional studies of pitrilysin and related M16A proteases., The Biochemical journal, 398 (1), 145-52 Abstract
  • Plummer LJ, Hildebrandt ER, Porter SB, Rogers VA, McCracken J, Schmidt WK (Feb 2006) Mutational analysis of the ras converting enzyme reveals a requirement for glutamate and histidine residues., The Journal of biological chemistry, 281 (8), 4596-605 Abstract
  • Kim S, Lapham AN, Freedman CG, Reed TL, Schmidt WK (Jul 2005) Yeast as a tractable genetic system for functional studies of the insulin-degrading enzyme., The Journal of biological chemistry, 280 (30), 27481-90 Abstract
  • Schmidt WK, Michaelis S (2004) Ste24p, Handbook of Proteolytic Enzymes, 2nd edition, Elsevier Academic Press, 460-465 pages, ISBN=0-12-079611-2 (bookchapter)
  • Schmidt WK, Michaelis S (2004) Axl1p, Handbook of Proteolytic Enzymes, 2nd edition, Elsevier Academic Press, 879-882 pages, ISBN=0-12-079612-0 (bookchapter)
  • Cadinanos J, Varela I, Mandel DA, Schmidt WK, Diaz-Perales A, Lopez-Otin C, Freije JM, AtFACE-2, a Functional Prenylated Protein Protease From Arabidopsis Thaliana Related to Mammalian Ras-converting Enzymes., The Journal of Biological Chemistry, 278(43), 42091-7, Oct 2003 Abstract
  • Cadinanos J, Schmidt WK, Fueyo A, Varela I, Lopez-Otin C, Freije JM, Identification, functional expression and enzymic analysis of two distinct CaaX proteases from Caenorhabditis elegans, Biochemical Journal, 370(Pt 3), 1047-54, March 2003 Abstract
  • Bergo MO, Gavino B, Ross J, Schmidt WK, Hong C, Kendall LV, Mohr A, Meta M, Genant H, Jiang Y, Wisner ER, Van Bruggen N, Carano RA, Michaelis S, Griffey SM, Young SG, Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect, Proceedings of the National Academy of Sciences of the United States of America., 99(20), 13049-54, October 2002 Abstract
  • Tam A, Schmidt WK, Michaelis S, The Multispanning Membrane Protein Ste24p Catalyzes CAAX Proteolysis And NH2-terminal Processing of the Yeast A-factor Precursor., The Journal of Biological Chemistry, 276(50), 46798-806, Dec 2001 Abstract
  • Ketchum CJ, Schmidt WK, Rajendrakumar GV, Michaelis S, Maloney PC, The yeast a-factor transporter Ste6p, a member of the ABC superfamily, couples ATP hydrolysis to pheromone export, Journal of Biological Chemistry, 276(31), 29007-11, 2001 Abstract
  • Leung GK, Schmidt WK, Bergo MO, Gavino B, Wong DH, Tam A, Ashby MN, Michaelis S, Young SG, Biochemical studies of Zmpste24-deficient mice, Journal of Biological Chemistry, 276(31), 29051-8, 2001 Abstract
  • Schmidt WK, Tam A, Michaelis S, Reconstitution of the Ste24p-dependent N-terminal proteolytic step in yeast a-factor biogenesis, Journal of Biological Chemistry, 275(9), 6227-33, 2000 Abstract
  • Loayza D, Tam A, Schmidt WK, Michaelis S, Ste6p mutants defective in exit from the endoplasmic reticulum (ER) reveal aspects of an ER quality control pathway in Saccharomyces cerevisiae, Molecular Biology of the Cell, 9(10), 2767-84, October 1998 Abstract
  • Schmidt WK, Tam A, Fujimura-Kamada K, Michaelis S, Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage, Proceedings of the National Academy of Sciences (USA), 95(19), 11175-80, 1998 Abstract
  • Romano JD, Schmidt WK, Michaelis S, The Saccharomyces Cerevisiae Prenylcysteine Carboxyl Methyltransferase Ste14p Is in the Endoplasmic Reticulum Membrane., Molecular Biology of the Cell, 9(8), 2231-47, Aug 1998 Abstract
  • Schmidt WK, Moore HP, Ionic Milieu Controls the Compartment-specific Activation Of Pro-opiomelanocortin Processing in AtT-20 Cells., Molecular Biology of the Cell, 6(10), 1271-85, Oct 1995 Abstract
  • Schmidt WK, Moore HP, Synthesis and targeting of insulin-like growth factor-I to the hormone storage granules in an endocrine cell line, Journal of Biological Chemistry, 269(43), 27115-24, 1994 Abstract
  • Chavez RA, Chen YT, Schmidt WK, Carnell L, Moore HP, Expression of exogenous proteins in cells with regulated secretory pathways, Methods in Cell Biology, 43 Pt A, 263-88, 1994 Abstract

Profile Details

Last Updated: 12/24/2007

COS Expertise ID #355375
Reference this profile directly: http://myprofile.cos.com/wschmidt