Prediction of nucleating sequences from amyloidogenic propensities of tau-related peptides.
Physical properties, including amyloid morphology, FTIR and CD spectra, enhancement of Congo red absorbance, polymerization rate, critical monomer concentration, free energy of stabilization, hydrophobicity, and the partition coefficient between soluble and amyloid states, were measured for the tau-related peptide Ac-VQIVYK amide (AcPHF6) and its single site mutants Ac-VQIVXK amide (X not equal Cys). Transmission electron microscopy showed that 15 out of the 19 peptides formed amyloid in buffer, with morphologies ranging from straight and twisted filaments to sheets and rolled sheets. Using principal component analysis (PCA), measured properties were treated in a comprehensive manner, and scores along the most significant principal components were used to define individual amino acid amyloidogenic propensities. Quantitative structure-activity modeling (QSAM) showed that residues with greater size and hydrophobicity made the largest contributions to the propensity of peptides to form amyloid. Using individual amino acid propensities, sequences within tau with high amyloid-forming potential were estimated and found to include 226VAVVR230 in the proline-rich region, 275VQIINK280 (PHF6) and 306VQIVYK311 (PHF6) within the microtubule binding region, and 392IVYK395 in the C-tail region of the protein. The results suggest that regions outside the microtubule-binding region may play important roles in tau aggregation kinetics or paired helical filament structure.
Department of Chemistry, The University of Texas at Dallas, P.O. Box 830688 Richardson, Texas 75083-0688, USA.
Federico A
FA
Rojas Quijano
Dana
D
Morrow
Barry M
BM
Wise
Francesco L
FL
Brancia
Warren J
WJ
Goux
D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D002942:Circular Dichroism; D003224:Congo Red; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D046529:Microscopy, Electron, Transmission; D009842:Oligopeptides / Q000737:chemistry*; D025341:Principal Component Analysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics; D016875:tau Proteins / Q000737:chemistry* / Q000648:ultrastructure
D000682:Amyloid; D009842:Oligopeptides; C510485:acetyl-valyl-glutaminyl-isoleucyl-valyl-tyrosyl-lysinamide; D016875:tau Proteins; D003224:Congo Red