Objective Protein misfolding and aggregation into amyloid fibrils is a hallmark of serious diseases such as Alzheimer´s, Familial Amyloidotic Polyneuropathy (FAP) and atherosclerosis. Amyloid fibrils can also be biologically functional. Bacterial and fungal amyloids are proposed to form a prominent protein fold early in evolution. It is unclear why many different proteins, which often assume stable functional quaternary structure under normal conditions, can convert into a common β-sheet rich amyloid aggregate. An important unanswered question is whether the molecular mechanisms of amyloid formation have been conserved in evolution. We will characterize these mechanisms using two very different proteins involved in amyloid diseases: apolipoprotein A-I (apoA-I), a helical protein that is important in atherosclerosis and familial amyloidosis, and transthyretin (TTR), a beta-sheet protein that forms amyloid in FAP. We will explore in detail the novel molecular mechanism of amyloid formation by human apoA-I , which will help design a strategy to block this process. We will further characterize amyloid formation in evolutionary diverse species using fish TTR as a model protein that, we previously showed, forms amyloid. Fish are the most biodiverse group of vertebrates that can adapt to broad range of external conditions; hence, they are particularly suitable to study the adaptation of protein structure/function. TTR amyloid formation will be characterized in two evolutionary distinct piscine species with different adaptation mechanisms: a modern Actinopterygii (sea bream) and an ancient Agnatha (lamprey). The role of sea bream TTR N-terminus, previously proposed to be important in amyloid formation, will be investigated and compared with human TTR. The results will provide sharper insights into amyloid formation by structurally and evolutionaly diverse proteins, and will help develop new strategies to block amyloid diseases such as apoA-I amyloidosis, atherosclerosis and FAP. Fields of science medical and health sciencesbasic medicineneurologydementiaalzheimermedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsprotein folding Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2013-IOF - Marie Curie Action: "International Outgoing Fellowships for Career Development" Call for proposal FP7-PEOPLE-2013-IOF See other projects for this call Funding Scheme MC-IOF - International Outgoing Fellowships (IOF) Coordinator CENTRO DE CIENCIAS DO MAR DO ALGARVE EU contribution € 328 141,00 Address UNIVERSIDADE DO ALGARVE 8005-139 FARO Portugal See on map Region Continente Algarve Algarve Activity type Research Organisations Administrative Contact Deborah Power (Prof.) Links Contact the organisation Opens in new window Total cost No data
