Download A dead-end street of protein folding

A dead-end street of protein folding?
András Perczel, Villő Pálfi and Péter Hudáky
Laboratory of Structural Chemistry and Biology, Institute of Chemistry; Eötvös University,
Budapest 112, P.O. Box 32, H-1518, HUNGARY
Amino acid sequences of globular proteins encode their 3D-structures linked to their biological
function. More evidence supports that for many proteins a second, well organized, but quite different 3Dstructure also exists. The latter types of conformers have an architecture similar to the aggregated amyloid-state
(Alzheimer disease). (Eakin, C. M.; et al. Nat Struct Mol Biol 2006, 13, 202-208.) Interestingly enough, the
amyloid-like aggregates are practically independent of the primary sequence of the protein. Thus, the driving
force of the structural shift induced global transformation from the original to disease related amyloid fold is
expected to lie in the protein backbone, common to all proteins.(Nelson, R. et al. Nature 2005, 435, 773-778.,
and Wright, C. F. etal. Nature 2005, 438, 878-881.) These structures show low sequence specificity and have the
common motif of multiple stranded -pleated sheets. For dozens of ordinary proteins misfolding becomes
possible due to slightly abnormal cellular conditions.
Using first principle calculations on typical and atypical backbone foldammres, it will be shown that the
-pleated sheet structure, the building block of amyloid fibers, is the thermodynamically most stable
supramolecular arrangement. Strong backbone-backbone type interactions operative between strands could
indeed be the driving force of such amyloid-like aggregation, nipping and wedging proteins to a dead-end!
Figure: The formation of ”amyloid” like supramolecular matrces from isolated -sheets is
energetically favoured. Thus, the aggregation of polypeptides should be regarded as a
”normal” energy driven process.
Related references:
C. F. Wright et al. Nature, 2005, 438, 878
C. M. Dobson. Nature Struct. Mol. Biol., 2006, 13, 295
R. Nelson et al. Nature, 2005, 435, 773
J. L. Jimenez et al. The EMBO J., 1999, 18, 815
A. Perczel et al. J.Comp.Chem., 2005, 26, 1155
A. Perczel et al. JACS., 2007, 129, 14959