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Elizabeth Miller
Assistant Professor
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Research

A key component of cellular biology is the correct deployment of every gene product to the correct sub-cellular compartment. Fully one third of the proteins made by eukaryotic cells transit through the secretory pathway and thus enter the endoplasmic reticulum (ER), which serves as the gateway to this endomembrane system. The ER can be likened to a protein factory, charged with an array of duties that include (i) assembly of new proteins into their correct quaternary assemblies, (ii) ensuring quality control by surveying for damaged proteins and directing their destruction, and (iii) sending the completed product on to the end consumer. This final step of protein egress from the ER is mediated by transport vesicles that are sculpted from the ER membrane through the coordinated action of a set of cytoplasmic "coat" proteins, known as the COPII coat. This coat complex simultaneously deforms the membrane into small spherical structures and populates the nascent vesicles with cargo proteins that are destined for forward traffic.

Research in the Miller lab is broadly aimed at understanding the rules that govern uptake of proteins into nascent vesicles, a process that is influenced by the presentation of address labels or sorting signals, by the folding state of the client protein and by the coat itself. We use the budding yeast, Saccharomyces cerevisiae, as a model system, which affords numerous biochemical, genetic, genomic and proteomic tools that can be brought to bear on this fundamental biological problem. By using such a tractable model system, we can rapidly discover new pathways and mechanisms that may be directly relevant to a number of human diseases, most notably cystic fibrosis and similar diseases of protein misfolding. Two main research arms of the Miller lab attack this problem from different angles: we probe the molecular functions of the coat proteins themselves; and we study the client proteins that must navigate the quality control checkpoint.

 

Representative Recent Publications
  • Copic, A., Latham, C.F., Horlbeck, M., D’Arcangelo, J.G. and Miller, E.A. (2012) ER cargo properties specify a requirement for COPII coat rigidity mediated by Sec13p Science 335(6074): 1359-1362.
  • Kung, L.F., Pagant, S., Futai, E., D’Arcangelo, J.G., Buchanan, R., Dittmar, J.C., Reid, R.J.D., Rothstein, R., Hamamoto, S., Snapp, E.L., Schekman, R. and Miller, E.A. (2012) Sec24p and Sec16p cooperate to regulate the GTP cycle of the COPII coat. EMBO J. 31(4): 1014-1027.
  • Pina, F.J., O’Donnell, A.F., Pagant, S., Piao, H.L., Miller, J.P., Fields, S., Miller, E.A. and Cyert, M. (2011) Hph1 and Hph2 are novel components of the Sec63/Sec62 post-translational translocation complex that aid in V-ATPase biogenesis. Eukaryotic Cell 10(1):: 63-71.
  • Pagant, S. and Miller, E.* (2011) Getting high on traffic: the biochemistry of intracellular transport. Cellular Logistics 1(1): 41-44.
  • Louie, R.J., Pagant, S., Youn, J.Y., Halliday, J.J., Huyer, G., Michaelis, S. and Miller, E.A. (2010) Functional rescue of a misfolded eukaryotic ATP-binding cassette (ABC) transporter by domain replacement J. Biol. Chem 285(46): 36225-36234.
  • Pagant, S., Halliday, J.J., Kougentakis, C. and Miller, E.A. (2010) Intragenic suppressing mutations correct the folding and intracellular traffic of misfolded mutants of Yor1p, a eukaryotic drug transporter J. Biol. Chem 285(47): 36304-36314.
  • Buchanan, R., Kaufman A., Kung-Tran, L. and Miller, E.A. (2010) Genetic analysis of Sec24p mutants suggests cargo binding is not cooperative during ER export. Traffic 11(8): 1034-1043.
  • Miller, E.A. and Barlowe, C. (2010) Regulation of coat assembly – sorting things out at the ER. Curr. Opin. Cell Biol. 22(4): 447-453.
  • Faso, C., Chen, Y.N., Tamura, K., Held, M., Zemelis, S., Marti, L., Saravanan, R., Hummel, E., Kung, L., Miller, E.A., Hawes, C. and Brandizzi, F. (2009) A missense mutation in the Arabidopsis COPII coat protein Sec24A induced the formation of clusters of the endoplasmic reticulum and Golgi apparatus. Plant Cell 21(11): 3655-71.
  • Copic, A., Dorrington, M., Pagant, S., Barry, J., Lee, M.C.S., Singh, I., Hartman, J.L. and Miller, E.A. (2009) Genome-wide analysis reveals novel pathways affecting ER homeostasis, protein modification and quality control. Genetics
  • Pagant, S. and Miller, E.A. (2009) COP-mediated vesicle transport. in Protein Trafficking : Mechanisms and Regulation (Landes Bioscience; Nava Segev, editor) 182(3): 757-769.
  • Pagant, S., Brovman, E.Y., Halliday, J.J. and Miller, E.A (2008) Mapping of interdomain interfaces required for the functional architecture of Yor1p, a eukaryotic ATP-binding cassette (ABC) transporter J. Biol. Chem 283(39): 26444-26451.
  • Lee, M.C.S, Moura, P.A., Miller, E.A. and Fidock, D.A. (2008) Plasmodium falciparum Sec24 marks transitional ER that exports a model cargo via a diacidic motif. Mol. Microbiol 68(6): 1535-1546.
  • Pagant, S., Kung, L, Dorrington, M, Lee, M.C.S. and Miller, E.A. (2007) Inhibiting ER-associated degradation of misfolded Yor1p does not permit ER export despite the presence of a diacidic sorting signal. Mol. Biol. Cell 18: 3398-3413.
  • Miller, E.A. (2007) Vesicle tethering: TRAPPing transport carriers. Current Biology 17(6): R211-R213.
  • Lee, M.C.S. and Miller, E.A. (2007) Molecular mechanisms of COPII vesicle formation. Stem. Cell Dev. Biol 18(4): 424-434.
  • Johnson, E.D., Miller, E.A. and Anderson, M.A. (2007) Dual location of a family of proteinase inhibitors within the stigmas of Nicotiana alata. Planta 225(5: 1265-1276.
  • Miller, E.A., Liu, Y., Barlowe, C. and Schekman, R. (2005) ER-Golgi transport defects are associated with mutations in the Sed5p-binding domain of the COPII coat subunit Sec 24p. Mol. Biol. Cell 16(8): 3719-3726.
  • Lee, M.C.S., Miller, E.A., Goldberg, J., Orci, L. and Schekman, R. (2004) Bi-directional protein transport between the ER and Golgi. Annual Review of Cell and Developmental Biology 20: 87-123.
  • Miller, E.A., Beilharz, T.H., Malkus, P.N., Lee, M.C.S., Hamamoto, S., Orci, L. and Schekman, R. (2003) Multiple cargo binding sites on the COPII subunit Sec24p ensure capture of diverse membrane proteins into transport vesicles. Cell 114(4): 497-509.
  • Miller, E., Antonny, B., Hamamoto, S. and Schekman, R. (2002) Cargo selection into COPII vesicles is driven by the Sec24p subunit. EMBO J. 21(22): 6106-6113.
  • Miller, E.A., Lee, M.C.S., Atkinson, A.H. and Anderson, M.A. (2000) Identification of a novel four-domain member of the potato inhibitor II family from the stigmas of Nicotiana alata. Plant Mol. Biol. 42(2): 329-33.
  • Miller, E.A., Lee, M.C.S. and Anderson, M.A. (1999) Identification and characterization of a prevacuolar compartment from the stigmas of Nicotiana alata. Plant Cell 11(8): 1499-1508 Miller, E.A. and Anderson, M.A. (1999) Uncoating the mechanisms of vacuolar protein transport. Trends Plant Sci. 4: 46-48.
Elizabeth Miller
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