Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, Schubert D, Riek R.
3D structure of Alzheimer's amyloid-beta(1-42) fibrils.
Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17342-7.
PubMed.
The work by Luhrs et al. truly is a tour de force that integrates hydrogen exchange/NMR studies, electron microscopy, thioflavin T-binding, MTT assays, and molecular modeling into studies of the structure of fibrils formed by wild-type Aβ42 and a variety of rationally designed mutants. The result is a provocative model of the organization of Aβ protofilaments, the component structures comprising the mature 10 nm amyloid-type fibrils.
Evaluation of the work requires answers to two questions: Is the model correct, and is the model relevant? Additional experimentation will be required to provide these answers.
The clever single (asymmetric) and multiple (symmetric) amino acid substitution experiments performed by Luhrs et al. yield data consistent with their initial postulation of two β-strand regions connected by a short turn. The molecular modeling studies produce a model with low root-mean-square deviation (RMSD) error, again suggesting consistency and correctness of the derived protofilament structure. However, as with any modeling endeavor, the results depend on the assumptions. For example, the Luhrs model assumes the correctness of a certain feature of an earlier model, that of Robert Tycko's group, and thus becomes a "model based on a model based on experimental data" (with apologies to Professor Dan Kirschner for stealing his line).
The Luhrs model also integrates experimental data suggesting Met35 is not involved in intersheet side-chain packing. However, substantial experimental data exist showing that Met35 oxidation interferes significantly with Aβ aggregation (e.g., see Hou et al., 2002; Hou et al., 2004; Butterfield and Boyd-Kimball, 2005; Palmblad et al., 2002; Bitan et al., 2003).
These studies emphasize an important structural role for Met35 in fibril formation, one that can be rationalized mechanistically by models such as that of the Tycko group and those derived by molecular dynamics simulations (Urbanc et al., 2004). The contribution of Met35 to fibril formation is consistent with the fact that fibril formation of the [35L]Aβ(1-42) peptides used in the study of Luhrs et al. occurred over a relatively long time period (two months).
The use of oxidized Aβ (Met35 sulfoxide) also raises the question of relevance. What is the primary structure of the Aβ peptide(s) in vivo that gives rise to fibrils? Are the fibrils thus formed structurally equivalent to those studied by Luhrs et al? Evidence suggests that the predominant Aβ species is not oxidized. In addition, a large and increasing body of work supports the hypothesis that the most potent neurotoxins in Alzheimer disease and other diseases (e.g., prion diseases, see Silveira et al., 2005) may be oligomers and not fibrils. It would be exciting and informative if the approach of Luhrs et al. were applied to an analysis of the structure and dynamics of oligomer formation.
In conclusion, the fine work of Luhrs et al. provides a wonderful working model of Aβ protofilament structure that is rich in testable hypotheses.
References:
Hou L, Kang I, Marchant RE, Zagorski MG.
Methionine 35 oxidation reduces fibril assembly of the amyloid abeta-(1-42) peptide of Alzheimer's disease.
J Biol Chem. 2002 Oct 25;277(43):40173-6.
PubMed.
Hou L, Shao H, Zhang Y, Li H, Menon NK, Neuhaus EB, Brewer JM, Byeon IJ, Ray DG, Vitek MP, Iwashita T, Makula RA, Przybyla AB, Zagorski MG.
Solution NMR studies of the A beta(1-40) and A beta(1-42) peptides establish that the Met35 oxidation state affects the mechanism of amyloid formation.
J Am Chem Soc. 2004 Feb 25;126(7):1992-2005.
PubMed.
Butterfield DA, Boyd-Kimball D.
The critical role of methionine 35 in Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity.
Biochim Biophys Acta. 2005 Jan 17;1703(2):149-56.
PubMed.
Palmblad M, Westlind-Danielsson A, Bergquist J.
Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers.
J Biol Chem. 2002 May 31;277(22):19506-10.
PubMed.
Bitan G, Tarus B, Vollers SS, Lashuel HA, Condron MM, Straub JE, Teplow DB.
A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization.
J Am Chem Soc. 2003 Dec 17;125(50):15359-65.
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.
Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, Caughey B.
The most infectious prion protein particles.
Nature. 2005 Sep 8;437(7056):257-61.
PubMed.
Comments
David Geffen School of Medicine at UCLA
The work by Luhrs et al. truly is a tour de force that integrates hydrogen exchange/NMR studies, electron microscopy, thioflavin T-binding, MTT assays, and molecular modeling into studies of the structure of fibrils formed by wild-type Aβ42 and a variety of rationally designed mutants. The result is a provocative model of the organization of Aβ protofilaments, the component structures comprising the mature 10 nm amyloid-type fibrils.
Evaluation of the work requires answers to two questions: Is the model correct, and is the model relevant? Additional experimentation will be required to provide these answers.
The clever single (asymmetric) and multiple (symmetric) amino acid substitution experiments performed by Luhrs et al. yield data consistent with their initial postulation of two β-strand regions connected by a short turn. The molecular modeling studies produce a model with low root-mean-square deviation (RMSD) error, again suggesting consistency and correctness of the derived protofilament structure. However, as with any modeling endeavor, the results depend on the assumptions. For example, the Luhrs model assumes the correctness of a certain feature of an earlier model, that of Robert Tycko's group, and thus becomes a "model based on a model based on experimental data" (with apologies to Professor Dan Kirschner for stealing his line).
The Luhrs model also integrates experimental data suggesting Met35 is not involved in intersheet side-chain packing. However, substantial experimental data exist showing that Met35 oxidation interferes significantly with Aβ aggregation (e.g., see Hou et al., 2002; Hou et al., 2004; Butterfield and Boyd-Kimball, 2005; Palmblad et al., 2002; Bitan et al., 2003).
These studies emphasize an important structural role for Met35 in fibril formation, one that can be rationalized mechanistically by models such as that of the Tycko group and those derived by molecular dynamics simulations (Urbanc et al., 2004). The contribution of Met35 to fibril formation is consistent with the fact that fibril formation of the [35L]Aβ(1-42) peptides used in the study of Luhrs et al. occurred over a relatively long time period (two months).
The use of oxidized Aβ (Met35 sulfoxide) also raises the question of relevance. What is the primary structure of the Aβ peptide(s) in vivo that gives rise to fibrils? Are the fibrils thus formed structurally equivalent to those studied by Luhrs et al? Evidence suggests that the predominant Aβ species is not oxidized. In addition, a large and increasing body of work supports the hypothesis that the most potent neurotoxins in Alzheimer disease and other diseases (e.g., prion diseases, see Silveira et al., 2005) may be oligomers and not fibrils. It would be exciting and informative if the approach of Luhrs et al. were applied to an analysis of the structure and dynamics of oligomer formation.
In conclusion, the fine work of Luhrs et al. provides a wonderful working model of Aβ protofilament structure that is rich in testable hypotheses.
References:
Hou L, Kang I, Marchant RE, Zagorski MG. Methionine 35 oxidation reduces fibril assembly of the amyloid abeta-(1-42) peptide of Alzheimer's disease. J Biol Chem. 2002 Oct 25;277(43):40173-6. PubMed.
Hou L, Shao H, Zhang Y, Li H, Menon NK, Neuhaus EB, Brewer JM, Byeon IJ, Ray DG, Vitek MP, Iwashita T, Makula RA, Przybyla AB, Zagorski MG. Solution NMR studies of the A beta(1-40) and A beta(1-42) peptides establish that the Met35 oxidation state affects the mechanism of amyloid formation. J Am Chem Soc. 2004 Feb 25;126(7):1992-2005. PubMed.
Butterfield DA, Boyd-Kimball D. The critical role of methionine 35 in Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity. Biochim Biophys Acta. 2005 Jan 17;1703(2):149-56. PubMed.
Palmblad M, Westlind-Danielsson A, Bergquist J. Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers. J Biol Chem. 2002 May 31;277(22):19506-10. PubMed.
Bitan G, Tarus B, Vollers SS, Lashuel HA, Condron MM, Straub JE, Teplow DB. A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization. J Am Chem Soc. 2003 Dec 17;125(50):15359-65. 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.
Silveira JR, Raymond GJ, Hughson AG, Race RE, Sim VL, Hayes SF, Caughey B. The most infectious prion protein particles. Nature. 2005 Sep 8;437(7056):257-61. PubMed.
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