Effect of proline mutations on the monomer conformations of amylin.
Biophys J
; 105(5): 1227-35, 2013 Sep 03.
Article
en En
| MEDLINE
| ID: mdl-24010666
ABSTRACT
The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic ß-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate ß-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various ß-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long ß-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit ß conformations and stabilize the α-helical conformation. Fewer substitutions do not have a significant inhibiting effect.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Prolina
/
Proteínas Mutantes
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Simulación de Dinámica Molecular
/
Polipéptido Amiloide de los Islotes Pancreáticos
/
Mutación
Tipo de estudio:
Health_economic_evaluation
Límite:
Animals
/
Humans
Idioma:
En
Año:
2013
Tipo del documento:
Article