Lim KH, Collver HH, Le YT, Nagchowdhuri P, Kenney JM.
Characterizations of distinct amyloidogenic conformations of the Abeta (1-40) and (1-42) peptides.
Biochem Biophys Res Commun. 2007 Feb 9;353(2):443-9.
PubMed.
By Brigita Urbanc Assembly of the Aβ protein into potentially neurotoxic aggregates is at the center of one of the leading hypotheses of Alzheimer disease. Two Aβ alloforms, Aβ40 and Aβ42, which are 40 and 42 amino acids long, are primary components of amyloid deposits, considered to be the hallmark of the disease. There is substantial in vitro, in vivo, as well as genetic evidence implicating Aβ42 to a significantly larger extent than Aβ40. Structural differences between Aβ40 and Aβ42 folded monomers and aggregates are a consequence of a relatively small primary structure difference, i.e., the additional amino acids Ile41 and Ala42 at the C-terminus of Aβ42. Consequently, understanding the effect of this difference on folding and aggregation may be the key to understanding mechanisms of toxicity and to developing therapeutic strategies.
It is known that the folded structure of Aβ strongly depends on the local environment. In a membrane-like environment, both alloforms form predominantly α-helical structure (1,2), while in an aqueous solution a collapsed coil was observed by Zhang et al. (3). In the present paper, Lim et al. use CD and NMR spectroscopy to address what structure Aβ40 and Aβ42 monomers assume in aqueous solution under amyloidogenic conditions on a wide temperature range. Their results show that both Aβ40 and Aβ42, with increasing temperature, undergo conformational transition from an unstructured conformation into β-sheet-like, monomeric intermediates. NMR data helped Lim et al. identify the regions 3-12 and 20-22 that underwent conformational changes to more extended structures. Aβ42 was found to be significantly more structured at the C-terminus compared to Aβ40.
At this point, I'd like to address the terminology used to describe Aβ conformations. At low temperatures, Aβ40 and Aβ42 are in a folded conformation, thus a term "random coil" should not be used because it implies a lack of specific amino acid contacts and not only a lack of secondary structure elements (such as α-helix and β-strand). In aqueous solution at low temperatures, Aβ folded conformations have a collapsed-coil structure (3). Random coil should be reserved only for high-temperature unfolded conformations, which on average lack specific amino acid contacts due to thermal fluctuations.
The present study by Lim et al., is important and timely. It is a logical progression of the work done by Gursky and Aleshkov (4) on the temperature dependence of Aβ40 peptide in water. Gursky and Aleshkov showed that a collapsed coil structure at low temperatures undergoes a structural transition into a β-strand-rich conformation. However, Gursky and Aleshkov could not confirm whether this transition was accompanied by aggregation into dimers, etc., or occurred while Aβ40 was still in a monomeric state. The present study by Lim et al. confirmed that this transition occurs in monomeric states of both Aβ40 and Aβ42. Our group predicted temperature-driven conformational transition from a collapsed coil to a β-strand-rich monomer conformation; we used a discrete molecular dynamics (DMD) approach to study Aβ42 folding (Figure 3 in 5). A central hydrophobic cluster (Leu17-Ala21), as well as the N-terminal region, were among the regions with a high β-strand propensity, in accord with the present study of Lim et al. Similarly, our group predicted a temperature-driven conformational change from an α-helix to a β-strand-rich monomer conformation in an environment where the hydrophobic effect can be neglected, i.e., water-free membrane-like environment (Fig.1 in 6).
Taking into consideration the free energy, such a transition can be expected because of the interplay between the potential energy and entropy of the folded structure. In an environment with a strong hydrophobic effect, low temperatures will favor collapsed-coil with specific contacts between hydrophobic side-chain atoms (and also between oppositely charged amino acids). Hydrogen bonding is less likely to take place at low temperatures because the backbone geometry of the collapsed coil does not make it energetically favorable for a hydrogen bond to form, and because forming a hydrogen bond is associated with an entropy loss. Thermal fluctuations at higher temperatures destabilize the collapsed coil and the hydrophobic contacts; this makes hydrogen bonding entropically more favorable and promotes a β-sheet-like structure which, in turn, lowers the potential energy. In an environment with negligible hydrophobic effect, the hydrogen bonding is predominant and will lead at low temperatures to the lowest potential energy state, i.e., α-helical structure. At higher temperatures the β-sheet-like monomeric conformations with higher potential energy will be more favorable.
Lim et al. found a difference between Aβ40 and Aβ42 monomer structures at the C-terminus, where Aβ42 but not Aβ40 seems to be well-structured. The existence of a well-defined turn at Gly37-Gly38 in a folded Aβ42 but not Aβ40 (and consequently a substantial β-strand propensity of the C-terminus of Aβ42) was predicted by our group using DMD simulations (7). In vitro evidence was obtained by Lazo et al. (8). They used limited proteolysis and mass spectroscopy to find that in region 1-39 the two peptides show identical results while the C-terminal region of Aβ42 was protease-resistant, indicating that the C-terminus of Aβ42 is structured. All these in vitro and in silico results appear consistent with the difference between Aβ40 and Aβ42 folded structure at the C-terminus that may give rise to different oligomerization pathways (9). This may represent an important target for therapeutic drug design strategies.
See also:
A. Lam, B. Urbanc, J.M. Borreguero, N.D. Lazo, D.B. Teplow, and H.E. Stanley. Discrete Molecular Dynamics Study of Alzheimer Amyloid beta-protein (Abeta) Folding. Proceedings of the 2006 International Conference on Bioinformatics & Computational Biology, 322--328 (2006).
References:
Coles M, Bicknell W, Watson AA, Fairlie DP, Craik DJ.
Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is?.
Biochemistry. 1998 Aug 4;37(31):11064-77.
PubMed.
Crescenzi O, Tomaselli S, Guerrini R, Salvadori S, D'Ursi AM, Temussi PA, Picone D.
Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain.
Eur J Biochem. 2002 Nov;269(22):5642-8.
PubMed.
Zhang S, Iwata K, Lachenmann MJ, Peng JW, Li S, Stimson ER, Lu Y, Felix AM, Maggio JE, Lee JP.
The Alzheimer's peptide a beta adopts a collapsed coil structure in water.
J Struct Biol. 2000 Jun;130(2-3):130-41.
PubMed.
Gursky O, Aleshkov S.
Temperature-dependent beta-sheet formation in beta-amyloid Abeta(1-40) peptide in water: uncoupling beta-structure folding from aggregation.
Biochim Biophys Acta. 2000 Jan 3;1476(1):93-102.
PubMed.
Urbanc B, Cruz L, Ding F, Sammond D, Khare S, Buldyrev SV, Stanley HE, Dokholyan NV.
Molecular dynamics simulation of amyloid beta dimer formation.
Biophys J. 2004 Oct;87(4):2310-21.
PubMed.
Urbanc B, Cruz L, Yun S, Buldyrev SV, Bitan G, Teplow DB, Stanley HE.
In silico study of amyloid beta-protein folding and oligomerization.
Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17345-50.
PubMed.
Lazo ND, Grant MA, Condron MC, Rigby AC, Teplow DB.
On the nucleation of amyloid beta-protein monomer folding.
Protein Sci. 2005 Jun;14(6):1581-96.
PubMed.
Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB.
Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways.
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5.
PubMed.
Comments
Drexel University
By Brigita Urbanc Assembly of the Aβ protein into potentially neurotoxic aggregates is at the center of one of the leading hypotheses of Alzheimer disease. Two Aβ alloforms, Aβ40 and Aβ42, which are 40 and 42 amino acids long, are primary components of amyloid deposits, considered to be the hallmark of the disease. There is substantial in vitro, in vivo, as well as genetic evidence implicating Aβ42 to a significantly larger extent than Aβ40. Structural differences between Aβ40 and Aβ42 folded monomers and aggregates are a consequence of a relatively small primary structure difference, i.e., the additional amino acids Ile41 and Ala42 at the C-terminus of Aβ42. Consequently, understanding the effect of this difference on folding and aggregation may be the key to understanding mechanisms of toxicity and to developing therapeutic strategies.
It is known that the folded structure of Aβ strongly depends on the local environment. In a membrane-like environment, both alloforms form predominantly α-helical structure (1,2), while in an aqueous solution a collapsed coil was observed by Zhang et al. (3). In the present paper, Lim et al. use CD and NMR spectroscopy to address what structure Aβ40 and Aβ42 monomers assume in aqueous solution under amyloidogenic conditions on a wide temperature range. Their results show that both Aβ40 and Aβ42, with increasing temperature, undergo conformational transition from an unstructured conformation into β-sheet-like, monomeric intermediates. NMR data helped Lim et al. identify the regions 3-12 and 20-22 that underwent conformational changes to more extended structures. Aβ42 was found to be significantly more structured at the C-terminus compared to Aβ40.
At this point, I'd like to address the terminology used to describe Aβ conformations. At low temperatures, Aβ40 and Aβ42 are in a folded conformation, thus a term "random coil" should not be used because it implies a lack of specific amino acid contacts and not only a lack of secondary structure elements (such as α-helix and β-strand). In aqueous solution at low temperatures, Aβ folded conformations have a collapsed-coil structure (3). Random coil should be reserved only for high-temperature unfolded conformations, which on average lack specific amino acid contacts due to thermal fluctuations.
The present study by Lim et al., is important and timely. It is a logical progression of the work done by Gursky and Aleshkov (4) on the temperature dependence of Aβ40 peptide in water. Gursky and Aleshkov showed that a collapsed coil structure at low temperatures undergoes a structural transition into a β-strand-rich conformation. However, Gursky and Aleshkov could not confirm whether this transition was accompanied by aggregation into dimers, etc., or occurred while Aβ40 was still in a monomeric state. The present study by Lim et al. confirmed that this transition occurs in monomeric states of both Aβ40 and Aβ42. Our group predicted temperature-driven conformational transition from a collapsed coil to a β-strand-rich monomer conformation; we used a discrete molecular dynamics (DMD) approach to study Aβ42 folding (Figure 3 in 5). A central hydrophobic cluster (Leu17-Ala21), as well as the N-terminal region, were among the regions with a high β-strand propensity, in accord with the present study of Lim et al. Similarly, our group predicted a temperature-driven conformational change from an α-helix to a β-strand-rich monomer conformation in an environment where the hydrophobic effect can be neglected, i.e., water-free membrane-like environment (Fig.1 in 6).
Taking into consideration the free energy, such a transition can be expected because of the interplay between the potential energy and entropy of the folded structure. In an environment with a strong hydrophobic effect, low temperatures will favor collapsed-coil with specific contacts between hydrophobic side-chain atoms (and also between oppositely charged amino acids). Hydrogen bonding is less likely to take place at low temperatures because the backbone geometry of the collapsed coil does not make it energetically favorable for a hydrogen bond to form, and because forming a hydrogen bond is associated with an entropy loss. Thermal fluctuations at higher temperatures destabilize the collapsed coil and the hydrophobic contacts; this makes hydrogen bonding entropically more favorable and promotes a β-sheet-like structure which, in turn, lowers the potential energy. In an environment with negligible hydrophobic effect, the hydrogen bonding is predominant and will lead at low temperatures to the lowest potential energy state, i.e., α-helical structure. At higher temperatures the β-sheet-like monomeric conformations with higher potential energy will be more favorable.
Lim et al. found a difference between Aβ40 and Aβ42 monomer structures at the C-terminus, where Aβ42 but not Aβ40 seems to be well-structured. The existence of a well-defined turn at Gly37-Gly38 in a folded Aβ42 but not Aβ40 (and consequently a substantial β-strand propensity of the C-terminus of Aβ42) was predicted by our group using DMD simulations (7). In vitro evidence was obtained by Lazo et al. (8). They used limited proteolysis and mass spectroscopy to find that in region 1-39 the two peptides show identical results while the C-terminal region of Aβ42 was protease-resistant, indicating that the C-terminus of Aβ42 is structured. All these in vitro and in silico results appear consistent with the difference between Aβ40 and Aβ42 folded structure at the C-terminus that may give rise to different oligomerization pathways (9). This may represent an important target for therapeutic drug design strategies.
See also:
A. Lam, B. Urbanc, J.M. Borreguero, N.D. Lazo, D.B. Teplow, and H.E. Stanley. Discrete Molecular Dynamics Study of Alzheimer Amyloid beta-protein (Abeta) Folding. Proceedings of the 2006 International Conference on Bioinformatics & Computational Biology, 322--328 (2006).
References:
Coles M, Bicknell W, Watson AA, Fairlie DP, Craik DJ. Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is?. Biochemistry. 1998 Aug 4;37(31):11064-77. PubMed.
Crescenzi O, Tomaselli S, Guerrini R, Salvadori S, D'Ursi AM, Temussi PA, Picone D. Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain. Eur J Biochem. 2002 Nov;269(22):5642-8. PubMed.
Zhang S, Iwata K, Lachenmann MJ, Peng JW, Li S, Stimson ER, Lu Y, Felix AM, Maggio JE, Lee JP. The Alzheimer's peptide a beta adopts a collapsed coil structure in water. J Struct Biol. 2000 Jun;130(2-3):130-41. PubMed.
Gursky O, Aleshkov S. Temperature-dependent beta-sheet formation in beta-amyloid Abeta(1-40) peptide in water: uncoupling beta-structure folding from aggregation. Biochim Biophys Acta. 2000 Jan 3;1476(1):93-102. PubMed.
Urbanc B, Cruz L, Ding F, Sammond D, Khare S, Buldyrev SV, Stanley HE, Dokholyan NV. Molecular dynamics simulation of amyloid beta dimer formation. Biophys J. 2004 Oct;87(4):2310-21. PubMed.
Urbanc B, Cruz L, Yun S, Buldyrev SV, Bitan G, Teplow DB, Stanley HE. In silico study of amyloid beta-protein folding and oligomerization. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17345-50. PubMed.
Lazo ND, Grant MA, Condron MC, Rigby AC, Teplow DB. On the nucleation of amyloid beta-protein monomer folding. Protein Sci. 2005 Jun;14(6):1581-96. PubMed.
Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB. Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5. PubMed.
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