Stable intrachain and interchain complexes of neurofilament peptides: a putative link between Al3+ and Alzheimer disease.
The etiologic role of Al3+ in Alzheimer disease has been controversial. Circular dichroism (CD) spectroscopic studies on two synthetic fragments of human neurofilament protein mid-sized subunit (NF-M), NF-M13 (KSPVPKSPVEEKG) and NF-M17 (EEKGKSPVPKSPVEEKG), and their alanine-substituted and/or serine-phosphorylated derivatives were carried out in an attempt to find a molecular mechanism for the effect of Al3+ to induce aggregation of neuronal proteins or their catabolic fragments. Al3+ and Ca2+ ions were found to induce beta-pleated sheet formation in the phosphorylated fragments. The cation sensitivity depended on the length and charge distribution of the sequence and site of phosphorylation. Al3+-induced conformational changes were irreversible to citric acid chelation, whereas Ca(2+)-induced conformational changes were reversible with citric acid. Studies of the alanine derivatives demonstrated which residues affected Al3+ or Ca2+ binding. Peptides containing at least one free (nonphosphorylated) serine residue were shown to form an intramolecular Al3+ complex, rather than an intermolecular one. In the intramolecular (intrachain) complex, the ligand function of the deprotonated serine hydroxyl was delineated [(Al.pepH-1)-type complex]. Ca2+ ions did not show a tendency for intramolecular complexing. The potential role of Al3+ in Alzheimer disease tangle and plaque formation is strongly suggested.
Hollósi
M
M
Department of Organic Chemistry, Eötvös University Budapest, Hungary.
Shen
Z M
ZM
Perczel
A
A
Fasman
G D
GD
D000535:Aluminum / Q000378:metabolism / Q000633:toxicity*; D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D008969:Molecular Sequence Data; D016900:Neurofilament Proteins / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011487:Protein Conformation
D016900:Neurofilament Proteins; D010446:Peptide Fragments; D000535:Aluminum; D002118:Calcium