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Merck
CN
  • Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils.

Comparative study of the stabilities of synthetic in vitro and natural ex vivo transthyretin amyloid fibrils.

The Journal of biological chemistry (2020-06-24)
Sara Raimondi, P Patrizia Mangione, Guglielmo Verona, Diana Canetti, Paola Nocerino, Loredana Marchese, Rebecca Piccarducci, Valentina Mondani, Giulia Faravelli, Graham W Taylor, Julian D Gillmore, Alessandra Corazza, Mark B Pepys, Sofia Giorgetti, Vittorio Bellotti
摘要

Systemic amyloidosis caused by extracellular deposition of insoluble fibrils derived from the pathological aggregation of circulating proteins, such as transthyretin, is a severe and usually fatal condition. Elucidation of the molecular pathogenic mechanism of the disease and discovery of effective therapies still represents a challenging medical issue. The in vitro preparation of amyloid fibrils that exhibit structural and biochemical properties closely similar to those of natural fibrils is central to improving our understanding of the biophysical basis of amyloid formation in vivo and may offer an important tool for drug discovery. Here, we compared the morphology and thermodynamic stability of natural transthyretin fibrils with those of fibrils generated in vitro either using the common acidification procedure or primed by limited selective cleavage by plasmin. The free energies for fibril formation were -12.36, -8.10, and -10.61 kcal mol-1, respectively. The fibrils generated via plasmin cleavage were more stable than those prepared at low pH and were thermodynamically and morphologically similar to natural fibrils extracted from human amyloidotic tissue. Determination of thermodynamic stability is an important tool that is complementary to other methods of structural comparison between ex vivo fibrils and fibrils generated in vitro Our finding that fibrils created via an in vitro amyloidogenic pathway are structurally similar to ex vivo human amyloid fibrils does not necessarily establish that the fibrillogenic pathway is the same for both, but it narrows the current knowledge gap between in vitro models and in vivo pathophysiology.

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纤溶酶 来源于人类血浆, lyophilized powder, ≥2.0 units/mg protein