Scenarios for Protein Aggregation.ppt

Scenarios for Protein Aggregation
Illustrations using A peptides and PrPC as examples
Ruxandra I. Dima
F. Massi (Columbia)
D. Klimov (GMU)
J. Straub (BU)
B. Tarus (BU)
M. S. Li (Poland)
(PrPC)
A-peptides
DIMACS meeting Rutgers University
April 20, 2006
Global Structure of amyloid fibrils
diameter = 4-12 nm (electron microscopy)
cross-b structure (strands perpendicular to long axis of fibril)
Å inter-strand spacing (along axis)
9 Å inter-sheet spacing (perpendicular on axis)
twist between adjacent strands
2-5 protofilaments (overall helical twist)
(X-ray fiber diffraction,solid state NMR)
Broad goal: Describe structures,
stabilities, ics from
monomers to fibrils
Energy landscape for monomeric folding
Monomer can misfold to
multiple conformations
Structural variations in the CBAs are imprinted in oligomers and fibrils
Aggregation Linked to diseases
Protein deposition diseases
* transmissible spongiform encephalopathies (TSE; Mad Cow Disease)
* Alzheimer’s disease, Parkinson’s disease
* diabetes (type II)
All these diseases = related to misfolding and protein aggregation
Misfolding into multiple amyloid conformations (strains)
Examples: prion proteins (TSE), Alzheimer’s, CWD
Question: What is the nature of the initial events in
oligomer formation?
Two broad scenarios: Illustrations using A peptides and PrPC
Current AD hypothesis: Soluble oligomers are neurotoxic
Scenarios for Fibrillization
N* = metastable
N* formation = partial unfolding
A and TTR
Prions
N* = stable
N* formation in prions = unfolding of N
(., D. Klimov and , Curr. Opin. Struct. Biol., 2003)
KG depends
on rate of
formation of
N* from N or
U
PrPc is metastable
with respect to PrP*
aggregation prone
particle
Cascade of events to Fibrils
Scenario I (Partial unfolding/ordering)
nA16-22(A16-22)n
Polydisperse
Oligomers
Heterogeneous Nucleation and Growth
On + kM
Differing
Supra-
molecular
Assembly
Heterogeneous Nuclei
KG = F(Seq