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J. Phys. Chem. B 2008, 112, 100-109
NMR Studies of the Zn2+ Interactions with Rat and Human β-Amyloid (1-28) Peptides in Water-Micelle Environment Elena Gaggelli,† Anna Janicka-Klos,‡ Elzbieta Jankowska,§ Henryk Kozlowski,*,‡ Caterina Migliorini,† Elena Molteni,† Daniela Valensin,† Gianni Valensin,*,† and Ewa Wieczerzak§ Department of Chemistry, UniVersity of Siena, Via Aldo Moro, 53-100 Siena, Italy, Faculty of Chemistry, UniVersity of Wrocław F. Joliot-Curie 14, 50-383 Wrocław, Poland, and Faculty of Chemistry, UniVersity of Gdan´ sk, 82-952 Gdan´ sk, Poland ReceiVed: July 3, 2007; In Final Form: October 2, 2007
Alzheimer’s disease is a fatal neurodegenerative disorder involving the abnormal accumulation and deposition of peptides (amyloid-β, Aβ) derived from the amyloid precursor protein. Here, we present the structure and the Zn2+ binding sites of human and rat Aβ(1-28) fragments in water/sodium dodecyl sulfate (SDS) micelles by using 1H NMR spectroscopy. The chemical shift variations measured after Zn2+ addition at T > 310 K allowed us to assign the binding donor atoms in both rat and human zinc complexes. The Asp-1 amine, His-6 Nδ, Glu-11 COO-, and His-13 N of rat Aβ28 all enter the metal coordination sphere, while His-6 Nδ, His13, His-14 N, Asp-1 amine, and/or Glu-11 COO- are all bound to Zn2+ in the case of human Aβ28. Finally, a comparison between the rat and human binding abilities was discussed.
The accumulation of protein precipitates at the end of degenerating brain neurons is the main feature of Alzheimer’s disease (AD). Their main constituent is a group of small peptide fragments called amyloid-β (Aβ), with lengths ranging from 39 to 43 amino acids, generated by proteolysis of the amyloid precursor protein (APP), a transmembrane glycoprotein.1 The fragments with 40 (Aβ40) and 42 (Aβ42) residues are most commonly encountered. Amyloid peptides in solution populate conformational states strongly dependent upon solvent and pH.2-8 Membrane mimicking environments at high (>7) and low ( 310 K, most of the proton resonances, particularly those of the His aromatic protons, which were very broad at T ) 298 K, returned to be detectable; 1D and 2D spectra were consequently recorded also at this temperature in order to get a better description of the zinc binding domain. The Zn-induced changes in chemical shift experienced by rAβ28 at T ) 318 K are reported in Figure 4. The most affected signals are within the flexible N-terminal region; in particular, the largest shifts are on the N-terminal Asp-1, His-6, His-14, and Glu-11; less marked effects are evident also on Glu-3, Val12, and Arg-13. This pattern of chemical shift variations clearly indicates Zn2+ coordination to His-6 and His-14 imidazoles, Asp-1 N-terminus, and Glu-11 side-chain carboxylate. Similar shifts were also observed for Ac-rAβ28 with the trivial exception of the effects recorded on Asp-1 HR and Hβ, since acetylating prevents metal binding to the terminal amino group. Moreover, the two peptides show almost identical shifts for His-6 aromatic protons, being the His-6 H shift much more pronounced than the His-6 Hδ one and suggesting metal binding of His-6 via Nδ in both peptides. On the contrary, a diverse behavior of His-14 was found. The His-14 aromatic protons, in fact, are almost equally shifted (∆δ ) -0.11 ppm for Hδ and -0.14 ppm for H) in the case of rAβ28, while for the corresponding protected peptide, His-14 Hδ is less shifted than H (∆δ ) -0.1 and -0.20 ppm), suggesting a diverse metal binding of His-14. In particular, the obtained results indicate zinc coordination to His-14 N for the unprotected fragment and to His-14 Nδ for the protected one.
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Figure 2. Aromatic region of 1H 1D spectra of the (A) rAβ28 0.9 mM in the presence of 1.0 Zn2+ equiv; (B) hAβ28 0.4 mM in the presence of 1.0 Zn2+ equiv; in H2O, 100 mM SDS at pH 7.5 at different temperatures.
Figure 3. Selected regions of the TOCSY spectrum of rAβ28 0.9 mM, 100 mM SDS at pH 7.5 and T ) 298 K: in the absence (black) and in the presence of 1.0 Zn2+ equiv (magenta). The broadening of selected amide protons (A) and the chemical shift variation (B) upon metal addition are shown.
The metal concentration dependence of chemical shifts allowed determining the dissociation constant Kd and the complex stoichiometry,65,66 by titrating the H protons of His-6 and His-14 (Figure 1s, Supporting Information). Standard regression analysis was used to fit the obtained exponential curves to the data, obtaining Kd in the range 200-400 µM at T ) 318 K. NOESY spectra recorded at 318 K provided additional information on the Zn2+ binding domain: long-range NOE were in fact detected among residues located at or very close to the metal binding site. In particular, Figure 5 shows the cross-peaks between His-14/Glu-11, His-14/Phe-10, His-6/Glu-11, and Asp1/Glu-11. All of the NOEs were converted into distance constraints which were used for structure calculation. On the best structures, an energy minimization and molecular dynamics simulation were performed in water in the presence of an SDS
micelle, in order to reproduce experimental conditions. The obtained structures (Figure 6) show two different well superimposed regions: (i) the C-terminal one with a rmsd calculated from Lys-16 to Ser-26 at 0.076 ( 0.032 nm for the backbone and 0.135 ( 0.053 nm for the heavy atoms and (ii) the N-terminus region including the metal binding site, with a rmsd calculated from Asp-1 to His-14 at 0.064 ( 0.019 nm for the backbone and 0.116 ( 0.043 nm for the heavy atoms. The R-helical structure observed for the free peptide between residues 20 and 24 is conserved also in the presence of the metal ion, suggesting that the C-terminus region is still interacting with the micelle and it is not perturbed by the metal ion, in agreement also with the negligible shift variations measured for that peptide region (Figure 4). Moreover, the CD experiments performed at temperatures in the range 298-328 K, in the presence of Zn2+, revealed that the R helix is not perturbed by the metal ion binding (data not shown).
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Figure 4. Histogram showing all of the obtained chemical shift variations (∆δ) for protons of rAβ28 (white) and Ac-rAβ28 (gray) 0.9 mM, 100 mM SDS at pH 7.5 and T ) 318 K in the absence and in the presence of 1.0 Zn2+ equiv.
Figure 5. Selected regions of the NOESY spectrum of rAβ28 0.9 mM, 100 mM SDS at pH 7.5 in the presence of 1.0 Zn2+ equiv. The long-range NOEs between residues located in the proximity of the binding site are circled.
hAβ(1-28) and Ac-hAβ(1-28). Both peptides were soluble in aqueous SDS micelles. The solutions remained stable over several weeks, without any evidence of aggregation or precipitation. NMR experiments demonstrated an helical conformation in the C-terminal region of both peptides, in agreement with previous investigations.56-59 From NOESY experiments, a family of structures was obtained (Figure 1B): the N-terminal region is completely disordered and flexible, while a well organized R-helical domain encompasses residues 16 to 24. The conformations determined for the human fragments are very similar to those obtained for the rat peptides; Figure 1C compares the two structures which are quite well superimposed
in the R-helical domain. As in the case of the rat peptides, the CD experiments showed absorptions typical of R-helical conformation (data not shown). The two (rat and human) amyloid CD spectra were very similar to each other revealing a similar interaction with the micellar surface, with a consequent structuring of the C-terminal region, identical for both peptides. Upon Zn2+ addition, several proton resonances were broadened at room temperature: the metal-induced effects were similar to those detected for the rat fragment (vide supra): (i) the TOCSY fingerprint region showed the disappearance of the same amide protons (Figure 2s), (ii) the His aromatic protons completely disappeared (Figure 2B), (iii) the Arg-5, Glu-11,
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Figure 6. Snapshots from the MD simulation of Zn2+-rAβ28 complex, superimposed with the structure obtained from experimental data. Two different regions are obtained: (left) the C-terminal one showing helical structural elements among 16-24 residues; (right) the N-terminal one illustrating the metal binding domain with Zn2+ tetrahedrally coordinated to Asp-1 NH2, His-6 Nδ, Glu-11 COO- and His-14 N. The figure was created with MOLMOL 2K.1.0.
Figure 7. Selected regions of the TOCSY spectrum of hAβ28 0.4 mM, 100 mM SDS at pH 7.5 and T ) 298 K: in the absence (black) and in the presence of 1.0 Zn2+ equiv. (magenta). The broadening of selected cross-peaks and the chemical shift variations upon metal addition are shown.
and Gln-15 spin-systems were completely lost (Figure 7), and (iv) a shift of -0.04 and 0.02 ppm was measured for Asp-1 and Val-12 HR, respectively (Figure 7). These findings are in agreement with what had been previously observed with the human full length Aβ40,35 where the His broadenings and the Asp-1 and Val-12 shifts were monitored by titrating the 1H13C HSQC spectra with Zn2+. 1H NMR experiments on metal complexes of hAβ and Ac28 hAβ28 were also performed at higher and lower temperatures in order to reduce the Zn2+-induced line broadening. While lowering the temperature to 278 K did not yield better spectra, raising the temperature to 328 K allowed detection of all three His aromatic protons (Figure 2B). In order to measure the Zn2+-induced changes in chemical shift, NOESY and TOCSY spectra were recorded also at T ) 328 K. At this temperature, all amide protons disappeared (also in the absence of the metal ion) because of the exchange with the solvent, and therefore no structure analysis could be
performed. The changes observed in the presence of 1.0 Zn2+ equivalents at T ) 328 K are reported in Figure 8. The most affected residues are His-6, Tyr-10, Glu-11, His-13, and His14; less pronounced but still significant effects are seen for Asp1, Ala-2, Glu-3, and Arg-5 resonances. The large His aromatic shifts strongly suggest the imidazole as the metal binding group, as previously found in other studies,23,29,31-33,35 indicating that the micelle-amyloid interactions do not perturb the metal binding ability. A different behavior was observed for His-6 with respect to the His-13-His-14 pair. His-13 and His-14 Hδ and H protons were approximately equally shifted, consistently with N as the donor atom in both residues, whereas the His-6 H (∆δ ) -0.22 ppm) was much more affected than Hδ (∆δ ) -0.10 ppm), indicating the involvement of Nδ rather than N in Zn2+ coordination. The behavior of unprotected hAβ28 and that of N-protected hAβ28 are compared in Figure 8: the largest deviations occur, as expected, at the N terminus, while residues between His-6
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Figure 8. Histogram showing all of the obtained chemical shift variations (∆δ) for protons of hAβ28 (white) and Ac-hAβ28 (gray) 0.4 mM, 100 mM SDS at pH 7.5 and T ) 328 K in the absence and in the presence of 1.0 Zn2+ equiv.
Figure 9. Snapshots from the MD simulation of Zn2+-hAβ28 complex, superimposed with the model based on experimental data. Global view of the peptide conformation (left); metal binding domain with Zn2+ coordinated to Asp-1 NH2, His-6 Nδ, Glu-11 COO-, His-13 N, and His-14 N (right). The figure was created with MOLMOL 2K.1.0.
and His-14 exhibit almost identical changes suggesting the presence of a single Zn2+ binding site. However, the same comparison reveals some peculiarity concerning the His residues. In fact, in the case of the acetylated fragment, His-6, His13, and His-14 display similar shifts on the aromatic protons, being H always more affected than Hδ, such that the involvement of different imidazole nitrogens (Nδ instead of N) was found for His-13 and His-14 for Ac-hAβ28. The shifts experienced by His H allow estimating Kd also for Zn2+-hAβ28. As in the case of the rat peptide, a metal titration was performed (Figure 3s), and a Kd in the range 3050 µM was found at T ) 328 K. Such a value is consistent
with previous results reporting a micromolar dissociation constant calculated at T < 310 K.31,35,67,68 As already mentioned, the structure of Zn2+-hAβ28 at higher temperatures could not be obtained; however, the CD experiments, performed at room and at higher temperatures on the Zn2+ complexes (Figure 4s), revealed that the metal ion does not interfere with the R-helical region which is present in the metal complexes. Moreover, the similarity between the CD spectra (in the presence and in the absence of the metal ion) led us to assume that the conformation of the C-terminal region is practically conserved between the free and the metal bound states. Therefore, a structural model (Figure 9) was built with
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Figure 10. Comparison of the chemical shift variations of hAβ28 (red) and rAβ28 (black) protons caused by the addition of 1.0 Zn2+ equiv at pH 7.5, T ) 328 K (human) and T ) 318 K (rat).
Zn2+ ion bound to the imidazoles, the N terminus, and the Glu11 carboxylate, while the C-terminus conformation was preserved as that found for the free peptide. Conclusions Addition of Zn2+ to rat and human Aβ28 in H2O/SDS selectively broadens the 1H NMR signals at T < 310 K, as already observed in previous NMR investigations on human Aβ40, Aβ28, and Aβ16.26,33,35,37 The strong broadening effects, observed in aqueous as well as in membrane-mimicking environments, suggest that metal binding is not affected by the presence of SDS micelles: the SDS-Aβ interaction in fact occurs at the C terminus, leaving the N-terminal region completely free to interact with Zn2+ (Figure 1). The Zn2+-induced line broadening has alternatively been attributed either to conformational exchange at a rate in intermediate regime with respect to the NMR time scale26,33,35,37 or to occurrence of aggregation phenomena.35 The similar effects monitored for the rat and human fragments led us to support an intermediate exchange regime rather than aggregation, since it has been reported that the rat Aβ is less susceptible to Zn2+induced aggregation than the human peptide.15 Moreover, while aggregation has been shown to be favored at 318 K rather than at 277 K,69,70 the line broadening is reduced by raising the temperature. The intermediate regime with respect to the NMR time scale may arise from (i) exchange between the free and the bound states, (ii) exchange between two or more binding sites, or (iii) exchange between different bound conformations. The first hypothesis was immediately ruled out by the fact that proton signals are still broadened after saturation of the rat and human Aβ28 zinc binding sites obtained with approximately two and one metal equivalents, respectively. Further metal additions yield negligible chemical shift variations at the investigated higher temperature (Figures 1s and 3s, Supporting Information), indicating the exclusive presence of the bound peptides. The presence of multiple Zn2+ binding modes was also excluded since the absence of metal binding donors such as the N-terminal (Ac-hAβ28, Ac-rAβ28) and the His-13 imidazole (rAβ28) did not affect the signal line broadening, suggesting the presence of a unique Zn2+ binding site as suggested earlier.22,26-38 The reduction of the NMR signal intensities induced by Zn2+ at room temperature was therefore ascribed to the presence of
different bound conformations. The largest effects were detected, not only for the residues involved in metal binding (His-6, Glu11, His-13, His-14) or those nearby (Arg-13, Gln-15), but also for many amide protons (Figure 2A and 3s). The full disappearance of amide protons of residues far away from the Zn2+ binding site (Leu-17, Val-18, Phe-19 for both peptides and Phe20 and Ala-21 for hAβ28) suggests that they experience two or more conformations since the amide protons are prone to large chemical shift variations depending on their chemical environment. The metal induced broadenings verified with either rat or human fragments largely limit the extraction of precise information on the Zn2+ binding sites, since most of the residues in the N-terminal region are vanished out by metal additions, and it may also explain why different results have previously been reported on those systems; however, the observed chemical shift variations at T ) 318 K can solve the ambiguity detected at room temperature. Raising the temperature up to 328 K yielded faster chemical exchange rates, and therefore, sharper NMR lines for Znamyloid peptide complexes were observed. Monitoring all proton signals at higher temperatures allowed delineating the metal effects on the investigated systems: in particular, the chemical shift variation analysis was performed at T ) 318 K and T ) 328 K for rat and human peptides, respectively. In fact, only at T ) 328 K, His-6, His-13, and His-14 H (in hAβ28) could be unambiguously assigned in the 1H NMR spectra. The addition of 1.0 Zn2+ equivalents resulted in large chemical shift variations on Asp-1, His-6, Glu-11, and His-14 for the rat peptide (Figure 4) and Asp-1, His-6, Tyr-10, Glu11, His-13, and His-14 for the human peptide (Figure 8). Moreover, for both systems, an upfield shift was detected for His aromatic protons and Asp-1 HR, while a downfield shift was found for Tyr-10 HR, Hβ and Glu-11 HR, Hβ, and Hγ. Such behavior can be accounted for by considering that, in the zinc histidine complexes, the carboxyl carbons shift downfield while the amino and imidazole nitrogens shift upfield.71 As a consequence, the upfield shift of Asp-1, His-6, His-13, and His14 can be attributed to Zn2+ binding at the terminal amino nitrogen and imidazole nitrogens, respectively, while the downfield shift observed on Glu-11 supports the participation of its carboxylate in the metal ion coordination. The large downfield changes observed for Tyr-10 can be ascribed to conformational changes caused by metal ion binding, rather than to direct
108 J. Phys. Chem. B, Vol. 112, No. 1, 2008 involvement of phenolate in coordination. This is supported by very small effects observed on the Tyr-10 H and Hδ. Furthermore, the shifts experienced by His aromatic protons allowed determining which imidazole nitrogen is bound to the metal ion; that is, His-6 coordinates via Nδ, and His-13 (when present) and His-14 coordinate through N. Acetylating of the N terminus yields the expected negligible effects observed for Asp-1. This clearly supports the involvement of the amino group in metal binding for both rat (Figure 4) and human (Figure 8) Aβ28. Previous reports had already suggested Zn2+ coordination to N terminus in the case of the human peptide,26,35 whereas NMR studies on Zn2+-rat peptide indicated the Arg-13 side chain NH2 as the additional binding donor, besides those of His-6 and His-14.43 This latter study, however, was performed in different experimental conditions (DMSO), which could give a strong impact on the obtained results. All four investigated systems display strong Zn2+-induced changes on Glu-11 (Figure 4 and 8): in particular, the Glu-11 Hγ’s are shifted downfield upon metal addition. These results strongly suggest binding of the Glu-11 carboxylate in both rat and human peptides, in agreement with previous NMR studies on hAβ16.33 Finally, a different Zn2+-imidazole coordination has been shown for His-13 and His-14 (Figure 4 and 8) for N-protected versus unprotected peptides: coordination of the terminal amino group favors the His-13 and His-14 metal binding via N rather than Nδ donor. Rat and human amyloid Aβ28 exhibit very similar effects in the presence of Zn2+, with the trivial difference of the His-13 missing in the rat peptide sequence. The additional involvement of His-13, in human peptide, in the metal coordination sphere, determines a distinctly more stable Zn2+ complex, which shows a dissociation constant at least 1 order of magnitude lower than the other. The comparison of the chemical shift variations of the rat and human peptides (Figure 10) has shown that the largest differences (besides those already mentioned on His-13) concern residues located at positions 5 and 10, which are the other two mutations found in the rat amyloid sequence, and these findings are revealing for the strong conformational changes occurring at these positions upon Zn2+ binding. The interaction with His13, in fact, is apparently determining a strong conformational rearrangement which involves Tyr-10. This may explain why many previous investigations had indicated Tyr-10 as a metal binding residue. Figure 10 also shows that, for hAβ28, both Asp-1 HR and Glu-11 Hγ exhibit smaller effects than those for rAβ28. Such a difference could be explained assuming that for the human peptides three and not two imidazole nitrogens participated in the metal coordination and the N-terminal amino group and Glu-11 carboxylate could play a minor role in the stabilization of the metal complex. The diverse temperature dependence of His-6 aromatic protons of human and rat peptides (Figure 2) suggests that, besides the larger affinity of human peptide-Zn2+ complex, there are also different kinetic processes possible. In particular, at T ) 310 K, the His-6 aromatic protons are in the fast exchange region of the NMR time scale only for the rat peptide, while such resonances are in the coalescence region for the human variant. On the basis of the obtained results, a structural model has been built for the human Zn2+ complex, while a structure of the Zn2+-rAβ28 complex has been determined by NMR. The obtained structures indicate the presence of two distinct domains: the N-terminal one where the metal binding site is
Gaggelli et al. located, and the C-terminal one, which is interacting with the micelle surface. The results, obtained at T > 310 K, describe the averaged structure of the two or more metal bound conformations which are in intermediate exchange regime respect to the NMR time scale. Interestingly, rat and human Aβ28 show different kinetic features, entering the exchange process the fast regime at physiological temperature (310 K) only for the rat peptide. The large broadening of Val-18, Phe19, Phe-20, Ala-21 amide protons which constitute the β1 sheet of the Aβ42 fibrils,72 suggest a significant conformational change in this hydrophobic region upon Zn2+ binding, which can therefore promote the β-sheet formation. The observed difference on kinetic and thermodynamic features of human and rat Zn2+ complexes could therefore be the key to understand the biophysical difference of the two peptide sequence. As pointed out in recent studies,73,74 the propensity to form aggregates is strongly influenced by the nature of the amino acid side chain, and in the case of Aβ-Zn2+ complexes, we found that the H13R mutation results in subtle affinity and kinetic differences between human and rat peptide suggesting its determinant role in the aggregation process of Aβ. Acknowledgment. We acknowledge the CIRMMP (Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine Paramagnetiche) and the MIUR (FIRB RBNE03PX83_003) for financial support. Supporting Information Available: 1H chemical shift of His-6 and His-14 H of rAβ28 as a function of zinc concentration. Finger print region of the TOCSY spectrum of hAβ28 0.4 mM, 100 mM SDS at pH 7.5 and T ) 298 K, in the absence and in the presence of 1.0 Zn2+ equiv, showing the broadening of selected amide protons upon metal addition. 1H chemical shift of His-6, His-13, and His-14 H of hAβ28 as a function of zinc concentration. CD spectra of 3 µM hAβ28 in presence of 1.0 Zn2+ equiv in H2O/SDS solutions, pH 7.5 at 298 (lower trace), 310, 318, and 328 K (upper trace). This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Selkoe, D. J. Physiol. ReV. 2001, 81, 741. (2) Barrow, C. J.; Zagorski, M. G. Science 1991, 253, 179. (3) Fraser, P. E.; Nguyen, J. T.; Surewicz, W. K.; Kirschner, D. A. Biophys. J. 1991, 60, 1190. (4) Hilbich, C.; Kisters-Woike, B.; Reed, J.; Masters, C. L.; Beyreuther K. J. Mol. Biol. 1991, 218, 149. (5) Burdick, D.; Soreghan, B.; Kwon, M.; Kosmoski, J.; Knauer, M.; Henschen, A.; Yates, J.; Cotman, C.; Glabe, C. J. Biol. Chem. 1992, 267, 546. (6) Otvos, L., Jr.; Szendrei, G. I.; Lee, V. M.; Mantsch, H. H. Eur. J. Biochem. 1993, 211, 249. (7) Talafous, J.; Marcinowski, K. J.; Klopman, J.; Zagorski, M. G. Biochemistry 1994, 33, 7788. (8) Hou, L.; Shao, H.; Zhang, Y.; Li, H.; Menon, N. K.; Neuhaus, E. B.; Brewer, J. M.; Byeon, I. J.; Ray, D. G.; Vitek, M. P.; Iwashita, T.; Makula, R. A.; Przybyla, A. B.; Zagorski, M. G. J. Am. Chem. Soc. 2004, 126, 1992. (9) Kirschner, D. A.; Inouye, H.; Duffy, L. K.; Sinclair, A.; Lind, M.; Selkoe, D. J. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 6953. (10) Gorevic, P. D.; Castano, E. M.; Sarma, R.; Frangione, B. Biochem. Biophys. Res. Commun. 1987, 147, 854. (11) Lovell, M. A.; Robertson, J. D.; Teesdale, W. J.; Campbell, J. L.; Markesbery, W. R. J. Neurol. Sci. 1998, 158, 47. (12) Maynard, C. J.; Bush, A. I.; Masters, C. L.; Cappai, R.; Li, Q. X. Int. J. Exp. Path. 2005, 86, 147. (13) Kozlowski, H.; Brown, D. R.; Valensin, G. Metallo Chemistry of Neurodegeneration Biological, Chemical and Genetic Aspects; RSC Publishing: Piccadilly, London, 2006. (14) Religa, D.; Strozik, D.; Cherny, R. A.; Volitakis, I.; Haroutunian, V.; Winblad, B.; Naslund, J.; Bush, A. I. Neurobiology 2006, 67, 69.
Human and Rat Zn2+ β-Amyloid (1-28) Complexes (15) Bush, A. I.; Pettingell, W. H.; Multhaup, G.; Paradis, M. D.; Vonsattel, J. P.; Gusella, J. F.; Beyreuther, K.; Masters, C. L.; Tanzi, R. E. Science 1994, 265, 1464. (16) Bush, A. I.; Moir, R. D.; Rosenkranz, K. M.; Tanzi, R. E. Science 1995, 268, 1921. (17) Huang, X.; Atwood, C. S.; Moir, R. D.; Hartshorn, M. A.; Vonsatell, J. P.; Tanzi, R. E.; Bush, A. I. J. Biol. Chem. 1997, 272, 26464. (18) Raman, B.; Ban, T.; Yamaguchi, K.; Sakai, M.; Kawai, T.; Naiki, H.; Goto, Y. J. Biol. Chem 2005, 280, 16157. (19) Karr, J. W.; Kaupp, L. J.; Szalai, V. A. J. Am. Chem. Soc. 2004, 126, 13534. (20) Esler, W. P.; Stimson, E. R.; Jennings, J. M.; Ghilardi, J. R.; Mantyh, P. W.; Maggio, J. E. J. Neurochem. 1996, 66, 723. (21) Morgan, D. M.; Dong, J.; Jacob, J.; Lu, K.; Apkarian, R. P.; Thiyagarajan, P.; Lynn, D. G. J. Am. Chem. Soc. 2002, 124, 12644. (22) Syme, C. D.; Nadal, R. C.; Rigby, S. E. J.; Viles, J. H. J. Biol. Chem. 2004, 279, 18169. (23) Garai, K.; Sengupta, P.; Sahoo, B.; Maiti, S. Biochem. Biophys. Res. Commun. 2006, 345, 210. (24) Cardoso, S. M.; Rego, A. C.; Pereira. C.; Oliveira, C. R. Neurotox. Res. 2005, 7, 273. (25) Talmard, C.; Guilloreau, L.; Coppel, Y.; Mazarguil, H.; Faller, P. ChemBioChem 2007, 8, 163. (26) Syme, C. D.; Viles, J. H. Biochim. Biophys. Acta 2006, 1764, 246. (27) Kowalik-Jankowska, T.; Ruta, M.; Wisniewska, K.; Lankiewicz, L. J. Inorg. Biochem. 2003, 95, 270. (28) Liu, S.; Howlett, G.; Barrow, C. J. Biochemistry 1999, 38, 9373. (29) Karr, J. W.; Akintoye, H.; Kaupp, L. J.; Szalai, V. A. Biochemistry 2005, 44, 5478. (30) Tickler, A. K.; Smith, D. G.; Ciccotosto, G. D.; Tew, D. J.; Curtain, C. C.; Carrington, D.; Masters, C. L.; Bush, A. I.; Cherny, R. A.; Cappai, R.; Wade, J. D.; Barnham, K. J. J. Biol. Chem. 2005, 280, 13355. (31) Mekmouche, Y.; Coppel, Y.; Hochgrafe, K.; Guilloreau, L.; Talmard, C.; Mazarguil, H.; Faller, P. ChemBiochem. 2005, 6, 1663. (32) Zirah, S.; Stefanescu, R.; Manea, M.; Tian, X.; Cecal, R.; Kozin, S. A.; Debey, P.; Rebuffat, S.; Przybylski, M. Biochem. Biophys. Res. Commun. 2004, 321, 324. (33) Zirah, S.; Kozin, S. A.; Mazur, A. K.; Blond, A.; Cheminant, M.; Segalas-Milazzo, I.; Debey, P.; Rebuffat, S. J. Biol. Chem. 2006, 281, 2151. (34) Ma, Q. F.; Hu, J.; Wu, W. H.; Liu, H. D.; Du, J. T.; Fu, Y.; Wu, Y. W.; Lei, P.; Zhao, Y. F.; Li, Y. M. Biopolymers 2006, 83, 20. (35) Danielsson, J.; Pierattelli, R.; Banci, L.; Graslund, A. FEBS J. 2007, 274, 46. (36) Stellato, F.; Menestrina, G.; Serra, M. D.; Potrich, C.; Tomazzolli, R.; Meyer-Klaucke, W.; Morante, S. Eur. Biophys. J. 2006, 35, 340. (37) Curtain, C. C.; Ali, F.; Volitakis, I.; Cherny, R. A.; Norton, R. S.; Beyreuther, K.; Barrow, C. J.; Masters, C. L.; Bush, A. I.; Barnham, K. J. J. Biol. Chem. 2001, 276, 20466. (38) Miura. T.; Suzuki, K.; Kohata, N.; Takeuchi, H. Biochemistry 2000, 39, 7024. (39) Shivers, B. D.; Hilbich, C.; Multhaup, G.; Salbaum, M.; Beyreuther, K.; Seeburg, P. H. EMBO J. 1988, 7, 1365. (40) Vaughan, D. W.; Peters, A. J. Neuropathol. Exp. Neurol. 1981, 40, 472. (41) Atwood, C. S.; Moir, R. D.; Huang, X.; Scarpa, R. C.; Bacarra, N. M.; Romano, D. M.; Hartshorn, M. A.; Tanzi, R. E.; Bush, A. I. J. Biol. Chem. 1998, 273, 12817. (42) Kang, J.; Lemaire, H. G.; Unterbeck, A.; Salbaum, J. M.; Masters, C. L.; Grzeschik, K. H.; Multhaup, G.; Beyreuther, K.; Mu¨ller-Hill, B. Nature 1987, 325, 733.
J. Phys. Chem. B, Vol. 112, No. 1, 2008 109 (43) Huang, J.; Yao, Y.; Lin, J.; Ye, Y. H.; Sun, W. Y.; Tang, W. X. J. Biol. Inorg. Chem. 2004, 9, 627. (44) Steward, J. M.; Young, J. D. Solid Phase Peptide Synthesis; Pierce Chemical Company: Rockford, IL, 1993. (45) The Millipore 9050 Plus PepSynthesizer Operator’s; Millipore Corporation: Billerica, MA, 1992. (46) Sole, N.; Barany, G. J. Org. Chem. 1992, 57, 5399. (47) Henry, G. D.; Sykes, B. D. Methods Enzymol. 1994, 239, 520. (48) Hwang, T. L.; Shaka, A. J. J. Magn. Reson. A 1995, 112, 275. (49) Gu¨ntert, P.; Mumenthaler, C.; Wu¨thrich, K. J. Mol. Biol. 1997, 273, 283. (50) Lindahl, E.; Hess, B.; van der Spoel, D. J. Mol. Model. 2001, 7, 306. (51) Berendsen, H.; van der Spoel, D.; van Drunen, R. Comput. Phys. Commun. 1995, 91, 43. (52) Jorgensen, W. L.; Tirado-Rives, J. J. Am. Chem. Soc. 1988, 110, 1657. (53) Berendsen, H.; Postma, J.; van Gunsteren, W. F.; Di Nola, A.; Haak, J. J. Chem. Phys. 1984, 81, 3684. (54) Ryckaert, J.; Ciccotti, G.; Berendsen, H. J. Comput. Phys. 1977, 23, 327. (55) Berendsen, H. Treatment of long range forces in Molecular Dynamics. In Molecular Dynamics and Protein Structure; Hermans, J., Ed.; Polycrystal Book Service: Western Springs, IL, 1995; p 18. (56) Shao, H.; Jao, S.; Ma, K.; Zagorski, M. G. J. Mol. Biol. 1999, 285, 755. (57) Poulsen, S. A.; Watson, A. A.; Fairlie, D. P.; Craik, D. J. J. Struct. Biol. 2000, 130, 142. (58) Coles, M.; Bicknell, W.; Watson, A. A.; Fairlie, D. P.; Craik, D. J. Biochemistry 1998, 37, 11064. (59) Fletcher, T. G.; Keire, D. A. Protein Sci. 1997, 6, 666. (60) McDonnell, P. A.; Opella, S. J. J. Magn. Reson. B 1993, 102, 120. (61) Henry, G. D.; Sykes, B. D. Methods Enzymol. 1994, 239, 520. (62) Du, Y.; Bales, K. R.; Dodel, R. C.; Liu, X.; Glinn, M. A.; Horn, J. W.; Little, S. P.; Paul, S. M. J. Neurochem. 1998, 70, 1182. (63) Matsubara, E.; Soto, C.; Governale, S.; Frangione, B.; Ghiso, J. Biochem. J. 1996, 316, 671. (64) Chen, Y. H.; Yang, J. T.; Chau, K. H. Biochemistry 1974, 13, 3350. (65) Reuben, J. J. Am. Chem. Soc. 1973, 95, 3534. (66) Vishwanath, C. K.; Easwaran, K. R. Biochemisty 1981, 20, 2018. (67) Garzon-Rodriguez, W.; Yatsimirsky, A. K.; Glabe, C. G. Bioorg. Med. Chem. Lett. 1999, 9, 2243. (68) Clements, A.; Allsop, D.; Walsh, D. M.; Williams, C. H. J. Neurochem. 1996, 66, 740. (69) Kusumoto, Y.; Lomakin, A.; Teplow, D. B.; Benedek, G. B. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 12277. (70) Yang, W. Y.; Larios, E.; Gruebele, M. J. Am. Chem. Soc. 2003, 125, 16220. (71) Kidambi, S. S.; Lee, D. K.; Ramamoorthy, A. Inorg. Chem. 2003, 42, 3142. (72) Lu¨hrs, T.; Ritter, C.; Adrian, M.; Riek-Loher, D.; Bohrmann, B.; Do¨beli, H.; Schubert, D.; Riek, R. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 17342. (73) Meinhardt, J.; Tartaglia, G. G.; Pawar, A.; Christopeit, T.; Hortschansky, P.; Schroeckh, V.; Dobson, C. M.; Vendruscolo, M.; Fandrich, M. Protein Sci. 2007, 16, 1214. (74) Chiti, F.; Stefani, M.; Taddei, N.; Ramponi, G.; Dobson, C. M. Nature 2003, 424, 805.