Does Aluminium Bind to Histidine? An NMR Investigation of Amyloid β12 and Amyloid β16 Fragments

• Published in: Chemical biology & drug design 2013-07, Vol.82 (1), p.48-59
• Main Authors: Narayan, Priya, Krishnarjuna, Bankala, Vishwanathan, Vinaya, Jagadeesh Kumar, Dasappa, Babu, Sudhir, Ramanathan, Krishna Venkatachala, Easwaran, Kalpathy Ramaier Katchap, Nagendra, Holenarasipur GunduRao, Raghothama, Srinivasarao
• Format: Article
• Language: English
• Subjects: aluminium interactions; Aluminum - chemistry; Aluminum - metabolism; Alzheimer's disease; Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; amyloid peptides; Aβ peptides; Histidine - metabolism; Magnetic Resonance Spectroscopy; metal binding; Molecular Sequence Data; NMR; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Protein Binding; Protein Structure, Tertiary
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12129

Aluminium and zinc are known to be the major triggering agents for aggregation of amyloid peptides leading to plaque formation in Alzheimer's disease. While zinc binding to histidine in Aβ (amyloid β) fragments has been implicated as responsible for aggregation, not much information is available on the interaction of aluminium with histidine. In the NMR study of the N‐terminal Aβ fragments, DAEFRHDSGYEV (Aβ12) and DAEFRHDSGYEVHHQK (Aβ16) presented here, the interactions of the fragments with aluminium have been investigated. Significant chemical shifts were observed for few residues near the C‐terminus when aluminium chloride was titrated with Aβ12 and Aβ16 peptides. Surprisingly, it is nonhistidine residues which seem to be involved in aluminium binding. Based on NMR constrained structure obtained by molecular modelling, aluminium‐binding pockets in Aβ12 were around charged residues such as Asp, Glu. The results are discussed in terms of native structure propagation, and the relevance of histidine residues in the sequences for metal‐binding interactions. We expect that the study of such short amyloid peptide fragments will not only provide clues for plaque formation in aggregated conditions but also facilitate design of potential drugs for these targets. NMR studies reveal non‐histidine binding site for aluminium in N‐terminal fragments (Aβ12 and Aβ16) of amyloid‐beta peptide implicated in Alzheimer disease. Structure similarity is maintained between the two fragments and the aluminium metal binding site is unaltered in the presence and absence of His13 and His14.