Amyloidogenesis is the self assembly of protein into a fibrillar aggregate termed amyloid. Amyloid is deposited in tissues as a consequence of certain diseases (e.g. Mad Cow's Disease, Familial Amyloid Polyneuropathy, Alzheimer's disease, Type II diabetes, etc. ) . The high molecular weight and insolubility of amyloid make it inaccessible to high resolution structural studies via conventional methods (X-ray crystallography and solution NMR). Electron microscopy and x-ray fiber diffraction have provided evidence for a cross-beta structure with beta-strands running prependicular to the long fibril axis. We employ a combination of solid state NMR (in collaboration with Alex Pines), hydrogen exchange, and limited proteolysis in an effort to obtain detailed structural information on amyloid fibrils and to understand the mechanism of formation.


The conversion of the prion protein from it's normally soluble predominantly a-helical form (PrPC) to an aggregated protease reseistant form (PrPsc) high in beta sheet content is responsible for numerous diseases (e.g. Creutzfeld-Jakobs, Bovine Spongiform Encephalopathy). PrPsc is infective. In vivo, Prpsc is able to convert PrPC to PrPsc which is the basis for the protein only hypothesis. Our efforts have focused on a model system, a 55mer mutated peptide derived from the Mouse Prion MoPrp 89-143 P101L which has been shown to be infective in transgenic mice.

Human Prion Protein Structure solved by Group Wuthrich
PNAS 97 (145) 2000

Preliminary solid state NMR experiments indicate that the MoPrP 89-143 P101L peptide undergoes conformational changes similar to the full length prion protein.


Transthyretin is a human plasma protein responsible for the transport of retinol (complexed with retinol binding protein). It is functional as a tetramer and is also the primary carrier of thyroxine in the CSF.

TTR Tetramer shown in blue, RBP shown in green.
Monaco, HL Rizzi, M. Coda, A. Science 268 (1039) 1995

TTR can be converted into amyloid fibrils in vitro by incubating at low pH. In collaboration with Jeff Kelly's group at TSRI, our group has shown that the native tetramer dissociated into a monomer, and the monomer partially unfolds before self assembling into amyloid fibrils at low pH.