dorsal/arxiv
View SchemaEarly events in insulin fibrillization studied by time-lapse atomic force microscopy
| Authors | A. Podesta', G. Tiana, P. Milani, M. Manno |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0502019 |
| URL | https://arxiv.org/abs/q-bio/0502019 |
| DOI | 10.1529/biophysj.105.068833 |
Abstract
The importance of understanding the mechanism of protein aggregation into insoluble amyloid fibrils relies not only on its medical consequences, but also on its more basic properties of self--organization. The discovery that a large number of uncorrelated proteins can form, under proper conditions, structurally similar fibrils has suggested that the underlying mechanism is a general feature of polypeptide chains. In the present work, we address the early events preceeding amyloid fibril formation in solutions of zinc--free human insulin incubated at low pH and high temperature. Aside from being a easy--to--handle model for protein fibrillation, subcutaneous aggregation of insulin after injection is a nuisance which affects patients with diabetes. Here, we show by time--lapse atomic force microscopy (AFM) that a steady-state distribution of protein oligomers with an exponential tail is reached within few minutes after heating. This metastable phase lasts for few hours until aggregation into fibrils suddenly occurs. A theoretical explanation of the oligomer pre--fibrillar distribution is given in terms of a simple coagulation--evaporation kinetic model, in which concentration plays the role of a critical parameter. Due to high resolution and sensitivity of AFM technique, the observation of a long-lasting latency time should be considered an actual feature of the aggregation process, and not simply ascribed to instrumental inefficency. These experimental facts, along with the kinetic model used, claim for a critical role of thermal concentration fluctuations in the process of fibril nucleation.
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"abstract": "The importance of understanding the mechanism of protein aggregation into\ninsoluble amyloid fibrils relies not only on its medical consequences, but also\non its more basic properties of self--organization. The discovery that a large\nnumber of uncorrelated proteins can form, under proper conditions, structurally\nsimilar fibrils has suggested that the underlying mechanism is a general\nfeature of polypeptide chains. In the present work, we address the early events\npreceeding amyloid fibril formation in solutions of zinc--free human insulin\nincubated at low pH and high temperature. Aside from being a easy--to--handle\nmodel for protein fibrillation, subcutaneous aggregation of insulin after\ninjection is a nuisance which affects patients with diabetes. Here, we show by\ntime--lapse atomic force microscopy (AFM) that a steady-state distribution of\nprotein oligomers with an exponential tail is reached within few minutes after\nheating. This metastable phase lasts for few hours until aggregation into\nfibrils suddenly occurs. A theoretical explanation of the oligomer\npre--fibrillar distribution is given in terms of a simple\ncoagulation--evaporation kinetic model, in which concentration plays the role\nof a critical parameter. Due to high resolution and sensitivity of AFM\ntechnique, the observation of a long-lasting latency time should be considered\nan actual feature of the aggregation process, and not simply ascribed to\ninstrumental inefficency. These experimental facts, along with the kinetic\nmodel used, claim for a critical role of thermal concentration fluctuations in\nthe process of fibril nucleation.",
"arxiv_id": "q-bio/0502019",
"authors": [
"A. Podesta\u0027",
"G. Tiana",
"P. Milani",
"M. Manno"
],
"categories": [
"q-bio.BM"
],
"doi": "10.1529/biophysj.105.068833",
"title": "Early events in insulin fibrillization studied by time-lapse atomic force microscopy",
"url": "https://arxiv.org/abs/q-bio/0502019"
},
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