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Understanding protein misfolding and aggregation by NMR

Final Report Summary - UPMAN (Understanding Protein Misfolding and Aggregation by NMR)

A detailed understanding of the processes responsible for the failure in achieving or in maintaining the normal functional structures of proteins is of crucial importance in the development of strategies to protect or enhance human health. To gain biologic al function, polypeptide chains generally need to fold into specific three- dimensional structures - their native states. Aberrant folding of proteins can lead to a range of other scenarios, including the development of highly organised and intractable aggregates that are deposited inside or outside cells. Such misfolding events are at the origins of a range of neurological and systemic diseases that increasingly compromise the quality and expectancy of life and the health resources of advanced societies. The focus of this application was the development of novel methods to study the structural slates of proteins that are particularly relevant to understand protein misfolding and aggregation. The species involved range from highly flexible unfolded monomers to soluble oligomers and precursors of fibrillar aggregates. In most of these states, polypeptide chains acquire structures that differ substantially from those of the native proteins that are accessible from conventional approaches of structural biology or from structural genomics procedures.

A range of complementary NMR approaches were developed. These approaches included a variety of NMR techniques, which were coupled with novel computational approaches able to define even the disorganised ensembles characteristic of some of the most interesting and biologically relevant species. These techniques were then applied to representative examples of the various types of proteins that are associated with misfolding diseases.

By generating structural information about prefibrillar states that are currently assumed to be the most toxic states of protein folding diseases, this STREP research project helps in the development of pharmaceutical products against some of the most debilitating conditions in modern society. However, in contrast to many other major diseases, the fundamental mechanism of protein misfolding and aggregation is less well studied. Therefore, studies aiming at providing a structural basis for protein misfolding and aggregation are not only at the forefront of innovative research but are also important assets for the life science and health priority area of the European Commission.