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Susan Michaelis, Ph.D.

Susan Michaelis, Ph.D.

Academic Titles: 
Professor
Position Title: 
Principal Investigator
410-955-7274 (Office)
410-955-8286 (Lab)
410-955-4129 (Fax)

Department of Cell Biology
Johns Hopkins University School of Medicine
725 N. Wolfe Street, 106 Biophysics
Baltimore, MD 21205

Research Topic : Progeria and lamin A processing by the ZMPSTE24 protease; ERAD and cytosolic protein quality control; yeast and mammalian 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 toidentify 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 in which degradation is too efficient (e.g. cystic fibrosis) or not efficient enough (e.g. neurological disorders like Parkinson’s)will rely on a detailed understanding of cellular protein quality control machinery.

 

 

Featured Article: Susan Michaelis on  "A Race Against Time"

 

Research Interest: 
Progeria and lamin A processing in mammalian cells; ubiquitin-proteasome mediated protein quality control in yeast.
Research Associates and Staff:
Name Position title Email Phone
Eric Spear, Ph.D. Research Associate espear3@jhmi.edu 410-955-8286
Lab Members:
Namesort descending Classification Email Phone
Khurts Shilagardi, Ph.D. Research Associate skhurts1@jhmi.edu 410-955-7274
Saba Shahzad Research Technologist sshahza1@jhmi.edu 410-955-7274
Selected Publications:
Ast, T., Michaelis, S., Schuldiner, M.  (2016) The protease Ste24 clears clogged translocons.  Cell 164:103-114
Maurer, M.J., Spear, E.D., Yu, A.T., Lee, E.J., Shahzad, S, and Michaelis, S.  (2016)  Degradation signals for ubiquitin-proteasome dependent cytosolic protein quality control (CytoQC) in yeast. (2016) G3:Genes, Genomes, Genetics (Epub ahead of print) (In Press).
Mehmood S., Marcoux J., Gault J., Quigley A., Michaelis S., Young S.G. Carpenter, E.P. and Robinson C.V.  Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24 (2016) Nature Chem. (In Press)
Kane, M. S., Linsday, 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 A 161:1599-1611 PMCID: PMC3740161
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, BJ., 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. 9:565-72 PMID: 23831759
Michaelis, S. and Hrycyna, C.A. (2013) A protease for the ages. Science 339:1529-30. PMID: 23539586
Barrowman, J., and Michaelis, S. (2013) The Ste24p Protease. In “Handbook of Proteolytic Enzymes,3nd Edition” (N. Rawlings, and G. S. Salvesen, eds.) Academic Press, Oxford, pp.668-676
Michaelis, S. and Hrycyna, C.A. (2013) A protease for the ages. Science 339:1529-30
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 (In Press).
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.
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.
Barrowman, J., Hamblet, C., Kane M.S., Michaelis, S. (2012) Requirements for efficient proteolytic cleavage of prelamin A by ZMPSTE24. PLoS ONE 7: e32120.
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.
Barrowman, J., and Michaelis, S. (2009) ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders. Biological Chemistry 390: 761-773.
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
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
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
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
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.
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.
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.