Structural and Computational Insights into Conformational Diseases: A Review
Pp. 134-182 (49)
Xavier Fernàndez-Busquets, Natalia S. de Groot and Salvador Ventura
Protein aggregation correlates with the development of several deleterious
human disorders such as Alzheimer's disease, Parkinson's disease, prion-associated
transmissible spongiform encephalopathies, type II diabetes and several types of cancers.
The polypeptides involved in these disorders may be globular proteins with a defined 3Dstructure
or natively unfolded proteins in their soluble conformations. In either case,
proteins associated with these pathogenesis all aggregate into amyloid fibrils sharing a
common structure, in which β-strands of polypeptide chains are perpendicular to the fibril
axis. Because of the prominence of amyloid deposits in many of these diseases, much effort
has gone into elucidating the structural basis of protein aggregation. A number of recent
experimental and theoretical studies have significantly increased our understanding of the
process. On the one hand, solid-state NMR, X-ray crystallography and single molecule
methods have provided us with the first high-resolution 3D structures of amyloids, showing
that they exhibit conformational plasticity and are able to adopt different stable tertiary
folds, with impact both their transmissibility and neurotoxicity. On the other hand, several
computational approaches have identified regions prone to aggregation in disease-linked
polypeptides, predicted the differential aggregation propensities of their genetic variants
and simulated the early, crucial steps of the oligomerization reaction. This review
summarizes these findings and their therapeutic relevance, as by uncovering specific
structural or sequential targets they may provide us with a means to tackle the debilitating
diseases linked to protein aggregation.
Aggregation prediction, Alzheimer’s disease, amyloid fibrils, atomic
force microscopy, computational biology, conformational diseases, electron
microscopy, fluorescence spectroscopy, hydrophobicity, neurodegenerative
diseases, oligomerization, Parkinson’s disease, prion, protein aggregation, protein folding, protein structure, scanning microscopy, single-molecule, solid-state
nuclear magnetic resonance, X-ray crystallography.
Departament de Bioquímica i Biologia Molecular, Facultat de Biocències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.