Susan Michaelis

Susan Michaelis, Ph.D.

Professor

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


Academic Titles

Professor

Research Topic

Progeria and lamin A processing; ubiquitin-proteasome mediated protein quality control.

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“

Associated Faculty

Name Title Email Phone
Eric Spear, Ph.D. Research Associate (Michaelis Lab) espear3@jhmi.edu 410-955-8286
Khurts Shilagardi, Ph.D. Research Associate (Michaelis Lab) skhurts1@jhmi.edu 410-955-7274

Lab Members

Name Classification Email Phone
Kamsi Odinammadu Student kodinam1@jhmi.edu 410-955-8286

Publications

  • Babatz, T.D., Spear, E. D, Xu, W., Sun, O. L., Nie, L., Carpenter. E.P., and Michaelis, S. (2020) Site Specificity Determinants for Prelamin A Cleavage by the Zinc Metalloprotease ZMPSTE24. J. Biol. Chem. (In Press)
  • Wood, K., Spear, E.D., Mossberg, O.W., Odinammadu, K., Xu, W., and Michaelis, S. (2020) Defining substrate requirements for cleavage of farnesylated prelamin A by the integral membrane zinc metalloprotease ZMPSTE24.  PLOS ONE (In Press)

  • Spear, E.D, Alford, R.F., Babatz, T.D., Wood, K., Mossberg, O.  Shilgardi, K., Odinammadu, K Gray, J., and Michaelis, S. (2019) A Humanized Yeast System to Analyze Cleavage of Prelamin A by ZMPSTE24. Methods 157:47-55

  • Preston G. M., Guerriero C. J., Metzger M.B., Michaelis S. and Brodsky J.L. 2018. Substrate insolubility dictates Hsp104-dependent endoplasmic reticulum associated degradation.  Mol. Cell 70:242-253 

  • Worman, H. J. and Michaelis, S. (2018). Permanently Farnesylated Prelamin A, Progeria and Atherosclerosis.  Circulation 183:283-6 PMC6056017

  • Spear E. D,. Hsu E.-T., Nie L., Carpenter E.P., Hrycyna C.A., and Michaelis S. (2018). ZMPSTE24 Missense mutations that cause progeroid diseases decrease prelamin A cleavage activity and/or  protein stability.  Disease Models and Mechanism 11:1-12 PMID 29794150

  • 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. G3:Genes, Genomes, Genetics 6:1853-66, PMC4938640.

  • Mehmood S., Marcoux J., Gault J., Quigley A., Michaelis S., Young S.G. Carpenter, E.P. and Robinson C.V. 2016. Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24. Nature Chem. 8:1152-1158. PMC 512 3592

  • 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.

  • 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.

  • 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.