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Primary Faculty  
Susan Michaelis, Ph.D.
Professor
Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe St., 106 Biophysics
Baltimore, MD 21205
Telephone: 410-955-7274 (Office)

10-955-8286 (Lab)

Fax: 410-955-4129
Email: michaelis@jhmi.edu
Website: N/A
Affiliations: • BCMB Graduate Program
  • Human Genetics Graduate Program
  • CMM Graduate Program


 

 

 

 

 

 

 

Research Topic : Progeria and lamin A processing; protein quality control mediated by the ubiquitin-proteasome system; mammalian and yeast cell biology.

The overall goal of our research is to dissect fundamental cellular processes relevant to human health and disease, using yeast and mammalian cell biology, biochemistry, and high-throughput genomic approaches. A current focus in our laboratory is the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS), which results from a mutation in the gene encoding the nuclear scaffold protein lamin A. Children with HGPS exhibit profound characteristics of aging, including hair loss, skin and bone defects, and heart disease. The mutant form of lamin A in HGPS patient cells is persistently modified by the lipid farnesyl, an aberrant situation, since normally cleavage by the ZMPSTE24 protease removes the farnesylated C-terminal tail of lamin A during biogenesis. We are examining the cell biology of lamin A processing, the molecular mechanisms of lamin A toxicity in HGPS, mechanistic features of the ZMPSTE24 membrane protease, therapeutic strategies, and the link between HGPS and normal aging.

We also study protein quality control mediated by the ubiquitin-proteasome system. Misfolded secretory and membrane proteins are efficiently degraded by ER-associated degradation (ERAD), while cytosolic quality control (CytoQC) pathways handle misfolded soluble proteins. Our goal is to identify the core cellular machinery involved in recognition of misfolded proteins, using model proteins as 'bait' in genome-wide yeast screens designed to uncover the eukaryotic ERAD and CytoQC machinery. Ultimately, devising treatment for protein misfolding diseases such as cystic fibrosis or Parkinson’s will require a detailed understanding of the cellular protein quality control machinery.

Selected Publications

Michaelis, S. and Hrycyna, C.A. (2013) A protease for the ages. Science 339:1529-30. PMID: 23539586

Kane, M. S., Lindsay, M. E., Judge, D. P., Barrowman, J., Ap Rys, C., Simonson, L., Dietz, H.C., Michaelis, S. (2013) LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset. American Journal of Medical Genetics, Part A 161: 1599-1611. PMID: 23666920

Snider J., Hanif A., Lee M. E., Jin K., Yu A. R., Graham C., Chuk M., Damjanovic D., Wierzbicka M., Tang P., Balderes D., Wong V., Jessulat, M., Darowski, K.D. San Luis, B-J., Shevelev, I. Sturley S. L., Boone C. , Greenblatt J. F., Zhang Z., Paumi C. M., Babu M., Park H.-O., Michaelis S., and I. Stagljar. (2013) Mapping the functional yeast ABC interactome. Nature Chem. Biol. [July 7; Epub ahead of print] PMID: 23831759

Barrowman J., Wiley, P.A., Hudon, S., Hrycyna, C.A. Michaelis, S. (2012) Human ZMPSTE24 disease mutations: residual enzymatic activity correlates with disease severity. Human Molecular Genetics 21:4084-4093. PMC3428156

Barrowman, J., Hamblet, C., Kane M.S., Michaelis, S. (2012) Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS ONE 7: e32120. PMC3280227

Michaelis, S. and Barrowman, J. Biogenesis of the Saccharomyces cerevisiae pheromome a-factor; from yeast mating to human disease. (2012) Microbiology and Molecular Biology Reviews 76: 626-651. PMC3429625

Barrowman, J., and Michaelis, S. (2009) ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders. Biological Chemistry 390: 761-773. . PMID: 19453269

Metzger MB, and Michaelis S. (2009) Analysis of Quality Control Substrates in Distinct Cellular Compartments Reveals a Unique Role for Rpn4p in Tolerating Misfolded Membrane Proteins Mol. Biol. Cell 20:1006-1019. PMC2633399

Metzger, M. B. Maurer, M. J., Dancy, B. M., and Michaelis, S. (2008) Degradation of a cytosolic protein requires ER-associated degradation (ERAD) machinery. J. Biol. Chem. 283:32302-32316. PMC2583311

Barrowman, J., Hamblet, C., George, C.M., and Michaelis, S. (2008) Analysis of prelamin A biogenesis reveals the nucleus to be a CaaX processing compartment. Mol. Biol. Cell 12:5398-5408 PMC2592638

Hudon, S. E., Coffinier, C., Michaelis, S., Fong, L. G., Young, S. G., and Hrycyna, C. A. (2008) HIV-Protease inhibitors block the enzymatic activity of purified Ste24p. Biochem Biophys Res Comm. 374:365-368 PMC2543933

Nakatsukasa, K., Huyer, G., Michaelis, S., and Brodsky J. L. (2008) Dissecting the ER-Associated Degradation of a Misfolded Polytopic Membrane Protein. Cell 132: 101-112. PMC2219389

Paumi, C. M., Menendez, J., Arnoldo, A, Engels, K, Iyer, K. R., Thaminy, S, Georgiev, O., Barral Y., *Michaelis, S., and *Stagljar, I. (2007) Mapping Protein-Protein Interactions for the Yeast ABC Transporter Ycf1p by Integrated Split-Ubiquitin Membrane Yeast Two-Hybrid (iMYTH) Analysis. Molecular Cell 26: 15-25. * Co-corresponding senior authors. PMID: 17434123

Mallampalli, M. P., Huyer, G., Bendale, P., Gelb, M. H., and Michaelis, S. (2005) Inhibiting Farnesylation Reverses the Nuclear Morphology Defect in a HeLa Cell Model for Hutchinson-Gilford Progeria Syndrome, Proc Natl. Acad Sci. USA 102:14416-14421. PMC1242289

Young, S. G. Fong, L., and Michaelis, S. (2005) Prelamin A, Zmpste24, misshapen cell nuclei, and progeria- new evidence suggesting that protein farnesylation could be important for disease pathogenesis. Journal of Lipid Research 46:2531-2558. PMID: 16207929

 

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Updated: 8/13/13

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