Associate Professor, Department of Biochemistry
The cellular protein pool is in constant flux. Correct maintenance of protein homeostasis in eukaryotic cells is vital for cell survival and is maintained by the coordinated action of protein biosynthesis, folding, repair, and degradation pathways. An important component of this proteostasis network is the ubiquitin-proteasome system (UPS) in the cytoplasm and nuclei of eukaryotic cells. It processes up to 80 % of intracellular proteins. Its activity is required for removal of damaged proteins and proteasome-mediated degradation of short-lived proteins regulates a wide variety of cellular pathways, such as cell cycle control, replication, transcription, metabolic adaptation, stress response, cell growth and differentiation. In consequence, impaired or overloaded UPS has been linked to a variety of human diseases such as cancer, neurodegenerative or immune system-related diseases.
The UPS consists of two collaborating modules, the ubiquitination machinery, which tags a substrate protein for degradation and the proteasome. The proteasome is one of the most complex enzymes found in cells and consists of more than 30 subunits and multiple associated proteins. Its activity is controlled at many levels to prevent unproductive protein turnover. The central building block of the proteasome is the proteolytic core cylinder (20S proteasome or core particle, CP) that needs to be activated by an associating complex, the 19S or regulatory particle, RP. Alternatively, the proteasome core cylinder can interact with non-canonical proteasome activators that mediate ATP- and ubiquitin-independent substrate degradation by the proteasome.
Our lab investigates the mechanism and cellular functions of the universally conserved proteasome activators Blm10/PA200. We found that these proteins represent stress inducible proteasome activators that regulate protein biosynthesis and mitochondrial activity. They enhance the degradation of a specific subset of proteasome substrates: intrinsically disordered proteins (IDPs). Most neurotoxic proteins are IDPs, such as huntingtin, tau and α- synuclein and loss of BLM10 in yeast or PA200 in mammalian cells results in increased aggregation and toxicity in cellular models for neurodegenerative diseases. Thus, understanding the mechanism of Blm10/PA200 proteasome activation could potentially result in novel strategies to combat neurodegenerative diseases.
Similar to neurodegeneration, the loss of functionality in aging cells is associated with proteostasis collapse. We reasoned that increased proteasome function might have a beneficial impact on the aging process and found that enhancement of proteasome activity extends the replicative lifespan of aging yeast, a well-established model system for aging research. Future studies are directed towards identifying cellular pathways in aging cells that benefit from improved proteasome activity.
Yang C, Schmidt M. Cutting through complexity: the proteolytic properties of alternate immunoproteasome complexes. Chem Biol. Apr 24;21(4):435 (2014)
Tar, K., Dange, T., Yang, C., Yao, Y., Bulteau, A.L., Salcedo, E.F., Braigen, S., Bouillaud, F., Finley, D., and Schmidt, M. (2014) Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1. J. Biol. Chem. 21: 12145- 12156 (2014)
Schmidt, M., Finley, D. Regulation of proteasome activity in health and disease. Biochim Biophys Acta. S0167: 310-318 (2014)
Schmidt, M., Kennedy, B.K. Aging: one thing leads to another. Curr Biol. 22:R1048-51 (2012)
Blickwedehl, J., Olejniczak, S., Cummings, R., Sarvaiya, N., Mantilla, A., Chanan-Khan, A., Pandita, T.K., Schmidt, M., Thompson, C.B., Bangia, N. The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation. Mol. Cancer Res. 10:937-944 (2012)
Short, M.K., Hallett, J.P., Tar, K., Dange, T, Schmidt, M., Moir, R., Willis, I.M. and Jubinsky, P.T. The yeast magmas ortholog pam16 has an essential function in fermentative growth that involves sphingolipid metabolism. PLoS One 7:e39428 (2012)
Dange, T., Smith, D., Noy, T., Rommel, P.C., Jurzitza, L., Legendre, A., Finley, D., Goldberg, A.L., and Schmidt, M. Blm10 promotes proteasomal substrate turnover by an active gating mechanism. J. Biol. Chem. 286: 42830-42839 (2011)
Kruegel, U., Robison, B., Dange, T., Kahlert, G., Delaney, J.R., Kotireddy, S., Tsuchiya, M., Tsuchiyama, S., Murakami, C.J., Schleit, J., Sutphin, G., Carr, D., TarK., Dittmar, D, Kaeberlein, M, KennedyB.K. and Schmidt, M. Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae. PLoS Genetics 7:e1002253 (2011) recommended by Faculty of 1000 Prime
Lopez, A., Tar, K, Kruegel, U, Dange, T, Guerrero Ros, I., and Schmidt, M. Proteasomal degradation of Sfp1 contributes to the repression of Ribosome Biogenesis during starvation and is mediated by the proteasome activator Blm10. Mol. Biol. Cell, 22: 528-540 (2011)
Wakata, A., Lee, H.M., Rommel, P., Toutchkine, A., Schmidt, M., and Lawrence, D.S. Simultaneous fluorescent monitoring of proteasomal subunit catalysis. J. Am. Chem. Soc. 132: 1578-1582 (2010)
Park S., Roelofs J., Kim W., Robert J., Schmidt M., Gygi S.P., Finley D. Hexameric assembly of the proteasomal ATPases is templated through their C termini. Nature 459: 866-870 (2009)
Schmidt, M. and Finley, D. Protease complexes. In: Robertson S, Editor “Encyclopedia of Life Sciences” London: Macmillan; (2007)
Crosas, B., Hanna, J., Kirkpatrick, D.S., Zhang, D.P., Tone, Y., Hathaway, N.A., Buecker, C., Leggett, D.S., Schmidt, M., King, R.W., Gygi,S.P., and Finley, D. Ubiquitin chain remodeling at the proteasome regulates protein degradation. Cell 127: 1401-1413 (2007)
Schmidt, M., Haas, W., Crosas, B., Santamaria, P.G., Gygi, S.P., Walz, T., and Finley, D. The HEAT repeat protein Blm10 regulates the yeast proteasome by capping the core particle. Nat. Struct. Mol. Biol. 12: 294-303 (2005) recommended by Faculty of 1000 Biology
Schmidt, M., Hanna, J., Elsasser, S., and Finley, D. Proteasome-associated proteins: regulation of a proteolytic machine. Biol. Chem. 386: 725-737. (2005)
Matur-Newman, R., Mobascher, A., Mangold, U., Koike, C., Diah, S., Schmidt, M., Finley, D., and Zetter, B.R. Antizyme Targets Cyclin D1 for Degradation J. Biol. Chem. 279: 41504-41510 (2004)
Leggett, D. S., Hanna, J., Borodovsky, A., Crosas, B., Schmidt, M., Baker, R.T., Walz, T., Ploegh, H. L., and Finley, D. M Multiple associated proteins regulate proteasome structure and function. Mol. Cell 10:495-505 (2002)
Witt, E., Zantopf, D., Schmidt, M., Kraft, R., Kloetzel, P. M., and Kruger, E. Characterisation of the newly identified human Ump1 homologue POMP and analysis of LMP7 (beta 5i) incorporation into 20 S proteasomes. J. Mol. Biol. 301:1-9 (2000)
Sijts, A. J., Ruppert, T., Rehermann, B., Schmidt, M., Koszinowski, U., and Kloetzel, P. M. Efficient generation of a hepatitis B virus cytotoxic T lymphocyte epitope requires the structural features of immunoproteasomes. J. Exp. Med. 191:503-514 (2000)
Braun, B. C., Glickman, M., Kraft, R., Dahlmann, B., Kloetzel, P. M., Finley, D., and Schmidt, M. The base of the proteasome regulatory particle exhibits chaperone-like activity. Nat. Cell Biol. 1:221-226 (1999) News and Views Nat. Cell Biol. 1999, 1: E97
Schmidt, M., Lupas, A. N., and Finley, D. Structure and mechanism of ATP-dependent proteases. Curr. Opin. Chem. Biol.3:584-91 (1999)
Schmidt, M., Zantopf, D., Kraft, R., Kostka, S., Preissner, R., and Kloetzel, P. M. Sequence information within proteasomal prosequences mediates efficient integration of beta-subunits into the 20 S proteasome complex. J. Mol. Biol. 288:117-128 (1999)
Salzmann, U., Kral, S., Braun, B., Standera, S., Schmidt, M., Kloetzel, P. M., and Sijts, A. Mutational analysis of subunit i beta2 (MECL-1) demonstrates conservation of cleavage specificity between yeast and mammalian proteasomes. FEBS Lett. 454:11-15 (1999)
Schmidt, M., and Kloetzel, P. M. Biogenesis of eukaryotic 20S proteasomes: the complex maturation pathway of a complex enzyme. Faseb J. 11:1235-1243 (1997)
More Information About Dr. Marion Schmidt
Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.
Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room 305
Bronx, NY 10461