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Hydrogen deuterium exchange and amyloid fibril formation


A range of human degenerative conditions, including Alzheimer's disease and type II diabetes, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils. Amyloid fibril formation requires often the population of at lea st partially unfolded states, these then go on to form aggregates that evolve into protofilaments which eventually give rise to mature amyloid fibrils Evidence from several groups suggests that the early formed aggregates, rather than the mature amyloid fi brils, are responsible for the onset of the disease Development of methodologies that would allow the study of the structural and dynamical properties of all the different species involved in the process of fibrillogenesis would be critical for understandi ng its mechanism and for guiding ongoing drug discovery efforts. During the applicant's initial Marie Curie Fellowship, a H/D exchange protocol developed to identify the structured core of the amyloid fibrils was extended to gain information on the dynamic s of the amyloid fibrils One of the objectives of this proposal is to further extend the applications of this H/D exchange protocol by characterizing the various oligomeric states accessible during the process of amyloid fibril formation Mutational studies on amyloidogenic proteins have provided information on the regions of the polypeptide chain that are likely to promote aggregation However, little is known about the role of the rest of the polypeptide chain. A second objective of this proposal is to carr y out the same H/D exchange study on different fragments of the same protein, all of them containing the region known to trigger amyloid fibril. This experimental set up is ÿ¡deal to evaluate the role of those parts of the polypeptide chain that aren't con sidered aggregation prone in the amyloid fibril process The overall goal of this proposal is to contribute to a better understanding of the mechanisms of protein misfolding and#

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Baldiri I Reixac, 10-12

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