Atomic View of a Toxic Amyloid Small Oligomer

Overview

Journal Science

Specialty Science

Date 2012 Mar 10

PMID 22403391

Citations 271

Authors

Arthur Laganowsky

Cong Liu

Michael R Sawaya

Julian P Whitelegge

Jiyong Park

Minglei Zhao

Anna Pensalfini

Angela B Soriaga

Meytal Landau

Poh K Teng

Duilio Cascio

Charles Glabe

David Eisenberg

Affiliations

Soon will be listed here.

Abstract

Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein αB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: β-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the β-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

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References

Greenwald J, Riek R . Biology of amyloid: structure, function, and regulation. Structure. 2010; 18(10):1244-60. DOI: 10.1016/j.str.2010.08.009. View

Shafrir Y, Durell S, Arispe N, Guy H . Models of membrane-bound Alzheimer's Abeta peptide assemblies. Proteins. 2010; 78(16):3473-87. PMC: 2976831. DOI: 10.1002/prot.22853. View

Streltsov V, Varghese J, Masters C, Nuttall S . Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease. J Neurosci. 2011; 31(4):1419-26. PMC: 6623621. DOI: 10.1523/JNEUROSCI.4259-10.2011. View

Goldschmidt L, Teng P, Riek R, Eisenberg D . Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc Natl Acad Sci U S A. 2010; 107(8):3487-92. PMC: 2840437. DOI: 10.1073/pnas.0915166107. View

Murzin A, Lesk A, Chothia C . Principles determining the structure of beta-sheet barrels in proteins. I. A theoretical analysis. J Mol Biol. 1994; 236(5):1369-81. DOI: 10.1016/0022-2836(94)90064-7. View

Kayed R, Head E, Thompson J, McIntire T, Milton S, Cotman C . Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003; 300(5618):486-9. DOI: 10.1126/science.1079469. View

Liu C, Sawaya M, Cheng P, Zheng J, Nowick J, Eisenberg D . Characteristics of amyloid-related oligomers revealed by crystal structures of macrocyclic β-sheet mimics. J Am Chem Soc. 2011; 133(17):6736-44. PMC: 3124511. DOI: 10.1021/ja200222n. View

Tomic J, Pensalfini A, Head E, Glabe C . Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction. Neurobiol Dis. 2009; 35(3):352-8. PMC: 2725199. DOI: 10.1016/j.nbd.2009.05.024. View

Last N, Rhoades E, Miranker A . Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity. Proc Natl Acad Sci U S A. 2011; 108(23):9460-5. PMC: 3111278. DOI: 10.1073/pnas.1102356108. View

10.

Lashuel H, Hartley D, Petre B, Walz T, Lansbury Jr P . Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature. 2002; 418(6895):291. DOI: 10.1038/418291a. View

11.

Dehle F, Ecroyd H, Musgrave I, Carver J . αB-Crystallin inhibits the cell toxicity associated with amyloid fibril formation by κ-casein and the amyloid-β peptide. Cell Stress Chaperones. 2010; 15(6):1013-26. PMC: 3024074. DOI: 10.1007/s12192-010-0212-z. View

12.

Sarsoza F, Saing T, Kayed R, Dahlin R, Dick M, Broadwater-Hollifield C . A fibril-specific, conformation-dependent antibody recognizes a subset of Abeta plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain. Acta Neuropathol. 2009; 118(4):505-17. PMC: 2737113. DOI: 10.1007/s00401-009-0530-3. View

13.

Salemme F, Weatherford D . Conformational and geometrical properties of beta-sheets in proteins. I. Parallel beta-sheets. J Mol Biol. 1981; 146(1):101-17. DOI: 10.1016/0022-2836(81)90368-5. View

14.

Meehan S, Knowles T, Baldwin A, Smith J, Squires A, Clements P . Characterisation of amyloid fibril formation by small heat-shock chaperone proteins human alphaA-, alphaB- and R120G alphaB-crystallins. J Mol Biol. 2007; 372(2):470-84. DOI: 10.1016/j.jmb.2007.06.060. View

15.

Tycko R . Solid-state NMR studies of amyloid fibril structure. Annu Rev Phys Chem. 2011; 62:279-99. PMC: 3191906. DOI: 10.1146/annurev-physchem-032210-103539. View

16.

Horwitz J . Alpha-crystallin can function as a molecular chaperone. Proc Natl Acad Sci U S A. 1992; 89(21):10449-53. PMC: 50356. DOI: 10.1073/pnas.89.21.10449. View

17.

Kirkitadze M, Bitan G, Teplow D . Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J Neurosci Res. 2002; 69(5):567-77. DOI: 10.1002/jnr.10328. View

18.

Picone P, Carrotta R, Montana G, Nobile M, San Biagio P, Di Carlo M . Abeta oligomers and fibrillar aggregates induce different apoptotic pathways in LAN5 neuroblastoma cell cultures. Biophys J. 2009; 96(10):4200-11. PMC: 2712196. DOI: 10.1016/j.bpj.2008.11.056. View

19.

Chimon S, Shaibat M, Jones C, Calero D, Aizezi B, Ishii Y . Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid. Nat Struct Mol Biol. 2007; 14(12):1157-64. DOI: 10.1038/nsmb1345. View

20.

Jang H, Arce F, Ramachandran S, Capone R, Lal R, Nussinov R . β-Barrel topology of Alzheimer's β-amyloid ion channels. J Mol Biol. 2010; 404(5):917-34. PMC: 7291702. DOI: 10.1016/j.jmb.2010.10.025. View