Structural defects and the diagnosis of amyloidogenic propensity

• Autores: Fernandez, Ariel; Kardos, Jozsef; Ridgway, Scott L.; Goto, Yuji; Berry, R. Stephen
• Año de publicación: 2003
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: AMYLOIDOSIS; HYDROGEN BONDS; PRIONS; PROTEIN STRUCTURE; STRUCTURAL WRAPPING
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Disease-related amyloidogenic propensity has been unexpectedly found in proteins driven to adopt a monomeric uncomplexed state at high concentrations under near-physiological conditions. This situation occasionally arises in new health treatments, such as kidney dialysis. Assuming that under such conditions a partial retention of native structure takes place, this work identifies a structural characteristic indicating amyloidogenic propensity: a high density of backbone hydrogen bonds exposed to water attack in monomeric structure. On this basis, we propose a diagnostic tool based on the identification of hydrogen bonds with a paucity of intramolecular dehydration or "wrapping." We use this predictor to identify potentially pathogenic mutations that foster amyloidogenic propensity in human prions. Such mutations either enhance the intramolecular dehydration of β-sheet hydrogen bonds, thus stabilizing the nucleus for rearrangement into the scrapie fold, or contribute to the destabilization of the cellular form by introducing additional underwrapped hydrogen bonds. Our predictions are consistent with known disease-related mutations and lead to a cogent explanation of the pathogenic nature of specific mutations affecting the cellular prion protein structural wrapping. On the other hand, a different wrapping of a very similar fold, mouse doppel, induces a dramatically different level of amyloidogenic propensity, suggesting that the packing within the fold, and not the fold itself, contains the signal for aggregation.
Fil: Fernandez, Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Kardos, Jozsef. University of Chicago. Department of Computer Science. Institute for Biophysical Dynamics; Estados Unidos
Fil: Ridgway, Scott L.. University of Chicago. Department of Computer Science. Institute for Biophysical Dynamics; Estados Unidos
Fil: Goto, Yuji. Osaka University and Core Research for EvolutionalScience and Technology. Institute for Protein Research; Japón
Fil: Berry, R. Stephen. University of Chicago. Department of Computer Science. Institute for Biophysical Dynamics; Estados Unidos