Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases.
Increasing evidence indicates that many peptides and proteins can be converted in vitro into highly organised amyloid structures, provided that the appropriate experimental conditions can be found. In this work, we define intrinsic propensities for the aggregation of individual amino acids and develop a method for identifying the regions of the sequence of an unfolded peptide or protein that are most important for promoting amyloid formation. This method is applied to the study of three polypeptides associated with neurodegenerative diseases, Abeta42, alpha-synuclein and tau. In order to validate the approach, we compare the regions of proteins that are predicted to be most important in driving aggregation, either intrinsically or as the result of mutations, with those determined experimentally. The knowledge of the location and the type of the "sensitive regions" for aggregation is important both for rationalising the effects of sequence changes on the aggregation of polypeptide chains and for the development of targeted strategies to combat diseases associated with amyloid formation.
Pawar
Amol P
AP
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Dubay
Kateri F
KF
Zurdo
Jesús
J
Chiti
Fabrizio
F
Vendruscolo
Michele
M
Dobson
Christopher M
CM
D019943:Amino Acid Substitution / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; D051843:Synucleins; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D016875:tau Proteins