James Shorter
Assistant Professor, Biochemistry and Biophysics

Cell Biology and Physiology Program

Address

805B Stellar Chance Labs
422 Curie Boulevard
Philadelphia, PA 19104-6059

Office tel.: 215 573-4256
Fax: 215 573-4257
E-mail: jshorter@mail.med.upenn.edu

Link(s)

University of Pennsylvania Health System faculty page

Biochemistry and Molecular Biophysics

EDUCATION

Keble College, Oxford University: BA, Biology, 1995.

Imperial Cancer Research Fund, University College London: PhD (Cell Biology), 2000.

Yale University: Post-Doctoral Studies (Graham Warren) (Cell Biology), 2000-2002.

Whitehead Institute of Biomedical Research, Massachusetts Institute of Technology: Post-Doctoral Studies (Susan Lindquist) Biochemistry and Genetics. 2002-2007

RESEARCH INTERESTS

We seek to understand the protein-folding pathways cells use to prevent, reverse, or even promote the formation of prion and amyloid fibers.

Key words: Prions, amyloids, chaperones, Hsp104, Aβ 42

Search PubMed for articles

DESCRIPTION OF RESEARCH

Amyloid fibers are self-perpetuating protein aggregates. They self-replicate their specific 'cross-β' conformation at their growing ends, by converting other copies of the same protein to the 'cross-β' amyloid form. When amyloid fibers grow and divide with high efficiency they can be infectious, and are then termed prions. Cells have evolved a sophisticated machinery to alleviate such aberrant protein aggregation. For example, protein-remodeling factors resolve protein aggregates, molecular chaperones prevent protein aggregation, osmolytes act as chemical chaperones, and degradation systems eliminate misfolded proteins. Nonetheless, these safeguards can be breached, especially as organisms age, and the consequences are often fatal. Prion and amyloid formation are associated with some of the most devastating neurodegenerative diseases confronting humankind, including Alzheimer's disease, Parkinson's disease, and variant Creutzfeldt-Jakob disease. Yet, surprisingly, it is becoming increasingly clear that prions and amyloids are not always a problem. In fact, several have been harnessed during evolution for adaptive purposes and feature in some of the most revolutionary new concepts in biology and evolution, including protein-based genetic elements, long-term memory formation, melanosome biogenesis, evolutionary capacitance and the revelation of cryptic genetic variation. We employ biochemistry and genetics to understand the enigmatic mechanistic interfaces that exist between protein-remodeling factors, molecular chaperones, small molecules and amyloid/prion fibers, and how these interfaces can be manipulated to divert pathogenic and promote beneficial phenotypic trajectories. In particular we seek to:

1. Define the mechanisms of Hsp104 function. Our major focus concerns Hsp104, a protein-remodeling factor of the AAA+ superfamily from yeast, which disaggregates denatured proteins and returns them to normal function. Hsp104 is also essential for the formation and inheritance of several yeast prions; protein-based genetic elements comprised of amyloid fibers that self-perpetuate alterations in protein form and function. Hsp104 can both construct and deconstruct self-replicating amyloid conformers of Sup35, which comprise the yeast prion [PSI+], and Ure2, which comprise the yeast prion [URE3]. We strive to understand the mechanistic basis of how Hsp104 structure enables these disaggregation activities and other prion-regulatory functions
2. Apply Hsp104 to disease-associated amyloidogenesis. Inexplicably, Hsp104 has no known homologue in metazoa. Indeed, whether mammals possess an analogous protein disaggregase (AAA+ protein or otherwise) remains an important open question. This is vexing, for it would seem that a protein that reverses protein aggregation and restores protein function, would be critical in our fight against several diseases caused by aberrant protein aggregation. Hence, we engineer and apply Hsp104 to metazoan systems to antagonize and reverse the proteotoxic aggregation pathways that are intimately connected with Parkinson's, Alzheimer's and Huntington's disease. We are also keen to identify whether there is a metazoan AAA+ protein that can perform a similar function to Hsp104.
3. Define how small molecules disrupt amyloid structure. Finally, we study a small molecule, 4,5-dianilinophthalimide, which dissolves Aβ42 fibers (that occur in Alzheimer's disease) and eliminates their neurotoxicity, and also disrupts prion structure and function. We are interested in defining the mechanisms by which this small molecule disrupts amyloid structure. Further, we seek to elucidate synergies between small molecules and protein-remodeling factors that may accelerate the disruption of specific amyloid oligomers and fibers.

RECENT PUBLICATIONS

Doyle, S. M., Shorter, J., Zolkiewski, M., Hoskins, J. R., Lindquist, S., and Wickner, S. (2007). Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity. Nat. Struct. Mol. Biol. 14, 114-122.

Shorter, J., and Lindquist, S. (2006). Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities. Mol. Cell 23, 425-438..

Shorter, J., and Lindquist, S. (2005). Prions as adaptive conduits of memory and inheritance. Nat. Rev. Genetics 6:435-450.

Shorter, J., and Lindquist, S. (2005). Navigating the ClpB channel to solution. Nat. Struct. Mol. Biol. 12:4-6.

Shorter, J., and Lindquist, S. (2004). Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304:1793-1797.

Lab

ROTATION PROJECTS