Analysis of the Role of the Conserved Disulfide in Amyloid Formation by Human Islet Amyloid Polypeptide in Homogeneous and Heterogeneous Environments.
Biochemistry
; 57(21): 3065-3074, 2018 05 29.
Article
em En
| MEDLINE
| ID: mdl-29697253
ABSTRACT
Human islet amyloid polypeptide (hIAPP) is a hormone secreted from ß-cells in the Islets of Langerhans in response to the same stimuli that lead to insulin secretion. hIAPP plays an adaptive role in glucose homeostasis but misfolds to form insoluble, fibrillar aggregates in type II diabetes that are associated with the disease. Along the misfolding pathway, hIAPP forms species that are toxic to ß-cells, resulting in reduced ß-cell mass. hIAPP contains a strictly conserved disulfide bond between residues 2 and 7, which forms a small loop at the N-terminus of the molecule. The loop is located outside of the cross ß-core in all models of the hIAPP amyloid fibrils. Mutations in this region are rare, and the disulfide loop plays a role in receptor binding; however, the contribution of this region to the aggregation of hIAPP is not well understood. We define the role of the disulfide by analyzing a collection of analogues that remove the disulfide, by mutation of Cys to Ser, by reduction and modification of the Cys residues, or by deletion of the first seven residues. The cytotoxic properties of hIAPP are retained in the Cys to Ser disulfide-free mutant. Removal of the disulfide bond accelerates amyloid formation in all constructs, both in solution and in the presence of model membranes. Removal of the disulfide weakens the ability of hIAPP to induce leakage of vesicles consisting of POPS and POPC. Smaller effects are observed with vesicles that contain 40 mol % cholesterol, although N-terminal truncation still reduces the extent of leakage.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Polipeptídeo Amiloide das Ilhotas Pancreáticas
Limite:
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos