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Faculty & Research

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Susan Michaelis

Department Affiliation Primary: Cell Biology
RankProfessor
Phone NumbersOffice: 410-955-7274
Lab: 410-955-8286
Fax: 410-955-4129
Emailmichaelis@jhmi.edu
School of Medicine AddressJohns Hopkins University School of Medicine
725 N. Wolfe St., 106 Biophysics
Baltimore MD 21205
Link to Lab Homepage
Susan Michaelis

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

We study fundamental cellular processes relevant to human disease. A major research 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.

Publications:

Michaelis S and Hrycyna CA.  (2013) A protease for the ages.  Science 339:1529-30.
PubMed Reference

Kane M S, Lindsay ME, Judge DP, Barrowman J, Ap Rys C, Simonson L, Dietz HC,  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.
PubMed Reference

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

Barrowman J, Wiley PA, Hudon S, Hrycyna CA, Michaelis,S. (2012) Human ZMPSTE24 disease mutations: residual enzymatic activity correlates with disease severity. Human Molecular Genetics  21:4084-4093.
PubMed Reference

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

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.
PubMed Reference

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

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.
PubMed Reference

Metzger MB, Maurer MJ, Dancy BM, and Michaelis S. (2008) Degradation of a cytosolic protein requires ER-associated degradation (ERAD) machinery. J. Biol. Chem. 283:32302-32316.
PubMed Reference

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

Hudon SE, Coffinier C, Michaelis S, Fong LG, Youn, SG, and Hrycyn, CA.  (2008)  HIV-Protease inhibitors block the enzymatic activity of purified Ste24p.  Biochem Biophys Res Comm. 374:365-368
PubMed Reference

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

Paumi CM, Menendez J, Arnoldo A, Engels K, Iyer KR, 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.
PubMed Reference

Mallampalli MP, Huyer G, Bendale P, Gelb MH, 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.
PubMed Reference

Young SG, 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.
PubMed Reference

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