The etiologic role ofAl3+ in Alzhelmer disease has been controversial. Circular dichroism (CD) spectrscopic studies on two synthetic Mfrgments of human neurofilament protein mid-sized subunit (NF-M), NF-M13 (KSPVPKSP-VEEKG) and NF-M17 (EEKGKSPVPKSPVEEKG), and their alanine-substituted and/or serine-phosphorylated derivatives were carried out in an attempt to find a molecular mechanm for the effect of A13+ to induce aggregation of neuronal proteins or their catabolic frments. AP+ and Ca2+ ions were found to induce a-pleated sheet formation in the phosphorylated fragments. The cation sensitivity depended on the length and charge distribution ofthe sequence and site ofphosphorylation. Al3+-induced conformational changes were irreversible to citric acid chelation, whereas Ca2+-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 A13+ complex, rather than an intermolecular one. In the intramolecular (intrachain) complex, the ligand function of the deprotonated serine hydroxyl was delineated [(Al'pepH I)-type complex]. Ca2+ ions did not show a tendency for intramolecular complexing. The potential role of Al3+ in Alzhelmer diseae tangle and plaque formation is strongly suggested.Aluminum has been recognized to be a neurotoxic agent, but its etiologic role in Alzheimer disease and other neurodegenerative diseases is still controversial (1-4). There is debate as to whether plaques precede tangles or vice versa. On the basis of a variety of physiological effects of A13+ in culture and animal systems and its consistent occurrence in neurofibrillary tangles (4, 5) and perhaps plaques (4, 6), it has been proposed that aluminum is a major risk factor in many neuronal dysfunctions. Others have questioned the etiologic significance of aluminum, mainly because of the failure of some researchers to find it in amyloid plaques by highly sensitive analytic techniques-i.e., laser microprobe mass analysis (7) and nuclear microscopy (8).There are several ways that enhanced aluminum levels may influence the structural or functional proteinous constituents of nerve cells. The In an attempt to find a molecular mechanism for the effect of aluminum to induce aggregation of neuronal proteins or their catabolic fragments, circular dichroism (CD) spectroscopic studies have been performed in our laboratories on synthetic fragments of human neurofilament mid-sized subunit protein (NF-M), KSPVPKSPVEEKG (NF-M13), and EEKGKSPVPKSPVEEKG (NF-M17), as well as on their alanine-substituted and/or serine-phosphorylated derivatives (15)(16)(17). CD spectra were recorded as described (18) and deconvoluted into secondary structural components by the convex constraint analysis method (19,20 and A13+ were found to induce the adoption of the (3-pleated sheet conformation in the C terminus in a low-dielectricconstant environment, in 2,2,2-...
The conformation of porcine serum ferric transferrin (Tf) and its stability against denaturation were studied by circular dichroism. [33][34][35][36][37]. Removal of the bound ferric ions (apo-Tf) did not alter the overall conformation, but there were subtle changes in local conformation based on its near-UV CD spectrum. The Tfs were stable between pH 3.5 and 11. Denaturation by guanidine hydrochloride (Gu-HCI) showed two transitions at 1.6 and 3.4 M denaturant. The process of denaturation by acid and base was reversible, whereas that by Gu-HCI was partially reversible. The irreversible thermal unfolding of Tfs began at temperatures above 60 "C and was not complete even at 80 "C. The bound irons (based on absorbance at 460 nm) were completely released at pH <4 or in Gu-HCI solution above 1.7 M, when the protein began to unfold, but they remained intact in neutral solution even at 85 "C. The NH2-and COOH-terminal halves of the Tf molecule obtained by limited trypsin digestion had CD spectra similar to the spectrum of native Tf, and the COOH-terminal fragment had more stable secondary structure than the NH,-terminal fragment.
The conformation of native and denatured Phaseolus coccineus var. rubronanus lectin was studied by circular dichroism (CD) and correlated to the hemagglutinating activity. The far-UV CD spectrum at 25 degrees C showed a broad, negative band around 223 nm and a positive one at 196 nm. CD data analysis of the lectin indicated a beta-sheet-rich protein. At high temperatures, the spectrum was blue-shifted with increasing magnitude; these changes correlated well with the loss of the activity. The conformation of lectin between pH 2 and 10 remained essentially unchanged. At pH 13 the CD spectrum resembled that of unordered form with a negative band near 200 nm and the activity was completely lost. The denatured lectin in 6 M guanidine hydrochloride would be renatured upon diluting the denaturant to 0.75 M; the changes in CD spectrum again correlated well with the loss of the activity. The effect of sodium dodecyl sulfate on the lectin was drastic; it sharply increased the alpha-helix at the expense of the beta-sheet and reduced the activity; the changes reached a plateau above 20 mM surfactant.
The conformation of pinellin was studied by circular dichroism, which showed a minimum at 223 nm and a double maximum at 198-200 nm. The protein was rich in beta-sheet (about 40%) with little alpha-helix, based on current CD analyses. It was stable between pH4 and 10 beyond which it unfolded reversibly, but in alkaline solution, prolongly stored at, say, pH 12, it became irreversibly denatured. Thermal denaturation indicated a transition between 55 degrees and 68 degrees C; the solution at 80 degrees C was partially renatured upon air-cooling back to room temperature. Addition of sodium dodecyl sulfate caused a sharp increase in alpha-helix, which leveled off at 0.25 mM surfactant.
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