Molecular modeling of the amyloid-β-peptide using the homology to a fragment of triosephosphate isomerase that forms amyloid <i>in vitro</i>
| dc.contributor.author | Contreras, CF | |
| dc.contributor.author | Canales, MA | |
| dc.contributor.author | Alvarez, A | |
| dc.contributor.author | De Ferrari, GV | |
| dc.contributor.author | Inestrosa, NC | |
| dc.date.accessioned | 2025-01-21T01:31:50Z | |
| dc.date.available | 2025-01-21T01:31:50Z | |
| dc.date.issued | 1999 | |
| dc.description.abstract | The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-beta-peptide (A beta), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conformations for the A beta peptide depending on the solvent and pH used. In general, they have suggested an alpha-helix conformation at the N-terminal domain and a beta-sheet conformation for the C-terminal domain. The structure of the complete A beta peptide (residues 1-40) solved by NMR has revealed that only helical structure is present in A beta. However, this result cannot explain the large beta-sheet A beta aggregates known to form amyloid under physiological conditions. Therefore, we investigated the structure of A beta by molecular modeling based on extensive homology using the Smith and Waterman algorithm implemented in the MPsrch program (Blitz server). The results showed a mean value of 23 % identity with selected sequences. Since these values do not allow a clear homology to be established with a reference structure in order to perform molecular modeling studies, we searched for detailed homology, A 28% identity with an alpha/beta segment of a triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three-dimensional structure was obtained. Then, multiple sequence alignment was performed considering A beta, TIM from C.tarralis and another five TIM sequences with known three-dimensional structures. We found a TIM segment with secondary structure elements in agreement with previous experimental data for A beta. Moreover, when a synthetic peptide from this TIM segment was studied in vitro, it was able to aggregate and to form amyloid fibrils, as established by Congo red binding and electron microscopy, The A beta model obtained was optimized by molecular dynamics considering ionizable side chains in order to simulate A beta in a neutral pH environment. We report here the structural implications of this study. | |
| dc.fuente.origen | WOS | |
| dc.identifier.issn | 0269-2139 | |
| dc.identifier.uri | https://repositorio.uc.cl/handle/11534/97153 | |
| dc.identifier.wosid | WOS:000084187200008 | |
| dc.issue.numero | 11 | |
| dc.language.iso | en | |
| dc.pagina.final | 966 | |
| dc.pagina.inicio | 959 | |
| dc.revista | Protein engineering | |
| dc.rights | acceso restringido | |
| dc.subject | Alzheimer's disease | |
| dc.subject | amyloid | |
| dc.subject | modeling | |
| dc.subject | triosephosphate isomerase | |
| dc.subject.ods | 03 Good Health and Well-being | |
| dc.subject.odspa | 03 Salud y bienestar | |
| dc.title | Molecular modeling of the amyloid-β-peptide using the homology to a fragment of triosephosphate isomerase that forms amyloid <i>in vitro</i> | |
| dc.type | artículo | |
| dc.volumen | 12 | |
| sipa.index | WOS | |
| sipa.trazabilidad | WOS;2025-01-12 |