Despite their molecular diversity, proteins possess the common property that, in general, they can rapidly and spontaneously self-assemble into elaborate three-dimensional structures that are required for their specific function. The ability of soluble protein or protein fragments to convert spontaneously into amyloid fibrils, which are related to a range of human disorders, is a very important biological phenomenon. Although soluble precursors of amyloidogenic proteins do not have any obvious sequence homology or common folding patterns, x-ray fiber diffractions data indicate that all amyloid fibrils share a characteristic cross-?-structure.1 This finding suggests that the key elements of the fibril formation process may be common to all proteins and that, therefore, a highly simplified system that is able to polymerize into ?-sheets can offer additional insights into the molecular details of amyloid fibril formation. Some rational designs based on alternating hydrophobic and hydrophilic residues have been found to have some success in identifying the interactions behind ?-sheet polymerization. To probe the interactions driving ?-sheet aggregation we have investigated the effect of specific residues on the propensity of a given sequence to form dimeric, antiparallel ?-strand. Small model systems offer important advantages for structural analysis. The smaller length of peptides compared with amyloidogenic proteins, allows more accurate fitting of the molecular structure within the fibers, once the dimensions of the protofilament are known. On these bases we have studied synthetic, hydrophobic, short peptides in order to identify the conformational changes involved in the formation of amyloid fibrils from the ?-aggregate precursor. References: 1.Rousseau, F. ; Serrano, L. Current Opinion in Structural Biology 2006, 16, 119-126 2.Thomas, R.J.; Radford, S.E.; Archives of Biochmistry and Biophysics 2008, 469, 100-117
POST-TRANSLATIONAL CONFORMATIONAL CHANGES THAT DISFAVOR THE ASSOCIATION PROCESS
E Fenude
2020
Abstract
Despite their molecular diversity, proteins possess the common property that, in general, they can rapidly and spontaneously self-assemble into elaborate three-dimensional structures that are required for their specific function. The ability of soluble protein or protein fragments to convert spontaneously into amyloid fibrils, which are related to a range of human disorders, is a very important biological phenomenon. Although soluble precursors of amyloidogenic proteins do not have any obvious sequence homology or common folding patterns, x-ray fiber diffractions data indicate that all amyloid fibrils share a characteristic cross-?-structure.1 This finding suggests that the key elements of the fibril formation process may be common to all proteins and that, therefore, a highly simplified system that is able to polymerize into ?-sheets can offer additional insights into the molecular details of amyloid fibril formation. Some rational designs based on alternating hydrophobic and hydrophilic residues have been found to have some success in identifying the interactions behind ?-sheet polymerization. To probe the interactions driving ?-sheet aggregation we have investigated the effect of specific residues on the propensity of a given sequence to form dimeric, antiparallel ?-strand. Small model systems offer important advantages for structural analysis. The smaller length of peptides compared with amyloidogenic proteins, allows more accurate fitting of the molecular structure within the fibers, once the dimensions of the protofilament are known. On these bases we have studied synthetic, hydrophobic, short peptides in order to identify the conformational changes involved in the formation of amyloid fibrils from the ?-aggregate precursor. References: 1.Rousseau, F. ; Serrano, L. Current Opinion in Structural Biology 2006, 16, 119-126 2.Thomas, R.J.; Radford, S.E.; Archives of Biochmistry and Biophysics 2008, 469, 100-117I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
