Final Activity Report Summary - METCLEF (Novel metal clusters in protein clefts) We were the first to observe that human serum transferrin could form fibrils. This 80 kDa bilobal protein transported iron (Fe3+), tightly bound to four amino acid side-chains and carbonate as a synergistic anion in closed interdomain clefts, one in each lobe. We showed that dehydration of iron transferrin on surfaces readily led to dendritic growth, fibril formation and release of iron which formed nanocrystallites of iron (hyd)oxide, i.e. rust, at periodic intervals along the length of the fibres. These findings might shed new light on iron deposition, which was thought to be involved in the pathogenesis of various neurodegenerative diseases. Furthermore, such reactions promoted the nanocrystallisation of manganese, which was also an essential metal, and bismuth, a metal used in therapy. In addition, we studied the behaviour of transferrin on surfaces using various microscopic techniques, which was never done previously. We observed the periodic nanocrystallisation of iron (hyd)oxide (rust) in a novel process involving dendritic outgrowths of the protein. Such periodic nanocrystallisation had not been previously observed. Neurodegenerative diseases such as Parkinson, Alzheimer and Huntington diseases and Hallervorden-Spatz syndrome were associated with the misregulation of iron regulation in the brain as well as with iron deposition, even though the causes were not firmly established. In case transferrin played a role in accumulation of iron in brain tissues, understanding the mechanism of this process would allow for the design of drugs which could disrupt transferrin aggregation and be used for treatment purposes.
