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Consecutive histidine repeats are chosen both by nature and by molecular biologists due to their high affinity towards metal ions. Screening of the human genome showed that transcription factors are extremely rich in His tracts. In this work, we examine two of such His-rich regions from forkhead box and MAFA proteins-MB3 (contains 18 His) and MB6 (with 21 His residues), focusing on the affinity and binding modes of Cu and Zn towards the two His-rich regions. In the case of Zn species, the availability of imidazole nitrogen donors enhances metal complex stability. Interestingly, an opposite tendency is observed for Cu complexes at above physiological pH, in which amide nitrogens participate in binding. [ABSTRACT FROM AUTHOR]

Amyloidogenic proteins are associated with severe neurodegenerative disorders afflicting millions of people worldwide. The main hallmarks of these diseases are the presence of amyloid plaques in the brain, primarily formed by fibrils of misfolded cellular proteins. The process leading to protein aggregation, is far from completely understood. However, it is well accepted that many factors are able to influence the morphology and kinetics of amyloids formation. In the last years, a plethora of studies have suggested that the aggregation process is greatly influenced by the interactions of these proteins with copper and membranes. Amyloidogenic proteins undergo large conformational changes in the presence of membranes and show the presence of stable α helix structures in the presence of high concentrations of unilamellar vesicles or detergent micelles. The regions involved in the helicoidal rearrangements are those which are critical for protein aggregation. In addition, the α helix structuring of amyloidogenic proteins may strongly affect copper binding, in terms of donor atoms and complex stability since metal binding domains are often located near regions experiencing transitions from random-coil to α helix conformations. [ABSTRACT FROM AUTHOR]

The basic knowledge about biological inorganic chemistry, thermodynamics and metal binding sites of metalloproteins is crucial for the understanding of their metal binding–structure–function relationship. Metal–peptide complexes are useful and commonly used models of metal–enzyme active sites, among which copper and zinc models are one of the most extensively studied. HENRYK is a peptide sequence present in numerous proteins, and serves as a potentially tempting binding site for Cu 2+ and Zn 2+ . Maybe more importantly, HENRYK also happens to be the first name of our group leader. The results of this work, which, at the first glance, might seem to be a ‘chemical scrabble’, went far beyond our expectations and surprised us with a novel, uncommon behavior of a Cu 2+ complex with a peptide with a histidine in position one. At low pH, the binding is a typical histamine-like coordination, but with the increase of pH, the imidazole nitrogen is moved to the axial position and replaced with an amide; at basic pH, the binding mode is a {NH 2 , 3N − } one in the equatorial plane. It is important to note, that no dimeric species are formed in between. Such binding is thermodynamically much more stable than a simple complex with histamine, and quite comparable to complexes with several possible imidazole anchoring sites. [ABSTRACT FROM AUTHOR]

The N-terminal fragment of Aβ (β = beta) peptide is able to bind essential transition metal ions like, copper, zinc and iron. Metal binding usually occurs via the imidazole nitrogens of the three His residues which play a key role in the coordination chemistry. Among all the investigated systems, the interaction between copper and Amyloid β assume a biological relevance because of the interplay between the two copper oxidation states, Cu(II) and Cu(I), and their involvement in redox reactions. Both copper ions share the ability to bind Amyloid β. A huge number of investigations have demonstrated that Cu(II) anchors to the N-terminal amino and His6, His13/14 imidazole groups, while Cu(I) forms a linear complex by coordinating to the His13 and His14 dyad. In this study we have analyzed Cu(I) interaction with the Amyloid β fragment encompassing the first 16 amino-acids. Our data were obtained by means of NMR spectroscopy which provided relevant structural details of the metal complexes. Our findings are consistent with the involvement of two or three His in the Cu(I) coordination sphere and indicate that His6 effectively participates to the metal binding. Cu(I) interaction with the N-terminal fragment of amyloid β. Unlabelled Image • His6, His13 and His14 are the primary Cu(I) binding sites of Aβ (β = beta). • Upon Cu(I) binding, Aβ16 undergoes to specific structural rearrangements. • In the metal complex His6 is close to the His13 His14 dyad. • His6 Nδ, His13 and His14 Nε are the Cu(I) binding donor atoms. • Ag(I) has strong potential in probing Cu(I) interaction with Aβ16. [ABSTRACT FROM AUTHOR]