Stubbs, Gerald J., Department of Biological Sciences

Gerald Stubbs
Department of Biological Sciences
5260A MRB III, 465 21st Av S 37232
615-322-2018 (office)
gerald.stubbs@vanderbilt.edu

Amyloid fibers are formed when normally soluble proteins change conformation to form insoluble filaments. These filaments can aggregate and deposit in tissues, causing severe damage
and even death. Many observations suggest that the amyloid structure is a fundamental feature of protein folding. More than 20 different clinical forms of amyloidosis have been recognized,
including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and a variety of diseases caused by prions. Mammalian prions are infectious protein aggregates
formed when the protein PrP folds into aberrant structures. They cause infectious, genetic, and sporadic illnesses, including Creutzfeldt-Jakob disease and bovine spongiform encephalopathy
“mad cow disease”.

Amyloid fibrils are long, unbranched, often twisted structures, typically 7-12 nm in diameter, characterized by a “cross-beta” X-ray fiber diffraction pattern. Although amyloid proteins share
the “cross-beta” structure (beta strands approximately at right-angles to the fiber axis), neither the fine details nor the ways in which the strands are assembled to form the structures are
known. Because of their complexity and insolubility, amyloid fibers have resisted characterization by protein crystallography and NMR. Structural studies are needed in order to answer
fundamental protein folding questions, to understand the physiology of amyloid accumulation, and for rational design of drugs to prevent or reverse amyloid formation, or to inhibit the physiological
effects of amyloids.

We are using primarily X-ray fiber diffraction methods to study the three-dimensional molecular structures of a variety of amyloids, including A-beta (Alzheimer’s) and both yeast and
mammalian prions, in collaboration with Dr Stanley Prusiner from UCSF. Students in our laboratory use the methods of structural biology, including synchrotron X-ray diffraction and
electron microscopy, combining approaches from biology, chemistry, mathematics, and physics.