title: Binding with nucleic acids or glycosaminoglycans converts soluble protein oligomers to amyloid.
abstract: Ample evidence suggests that almost all polypeptides can either adopt a native structure (folded or intrinsically disordered) or form misfolded amyloid fibrils. Soluble protein oligomers exist as an intermediate between these two states, and their cytotoxicity has been implicated in the pathology of multiple human diseases. However, the mechanism by which soluble protein oligomers develop into insoluble amyloid fibrils is not clear, and investigation of this important issue is hindered by the unavailability of stable protein oligomers. Here, we have obtained stabilized protein oligomers generated from common native proteins. These oligomers exert strong cytotoxicity and display a common conformational structure shared with known protein oligomers. They are soluble and remain stable in solution. Intriguingly, the stabilized protein oligomers interact preferentially with both nucleic acids and glycosaminoglycans (GAG), which facilitates their rapid conversion into insoluble amyloid. Concomitantly, binding with nucleic acids or GAG strongly diminished the cytotoxicity of the protein oligomers. EGCG, a small molecule that was previously shown to directly bind to protein oligomers, effectively inhibits the conversion to amyloid. These results indicate that stabilized oligomers of common proteins display characteristics similar to those of disease-associated protein oligomers and represent immediate precursors of less toxic amyloid fibrils. Amyloid conversion is potently expedited by certain physiological factors, such as nucleic acids and GAGs. These findings concur with reports of cofactor involvement with disease-associated amyloid and shed light on potential means to interfere with the pathogenic properties of misfolded proteins.
authors.affiliation: Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Di Domizio
authors.affiliation: Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Stagg
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030.
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.affiliation: Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030. Electronic address: wcao@mdanderson.org.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
mesh_terms: D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D002234:Carbodiimides / Q000494:pharmacology; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008744:Methylamines / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D012313:RNA / Q000378:metabolism*; D012995:Solubility
chemical_list: C569779:1-(3-dimethylaminopropyl)-dimethylaminopropyl-ethylcarbodiimide hydrochloride; D058227:Amyloidogenic Proteins; D002234:Carbodiimides; D003432:Cross-Linking Reagents; D006025:Glycosaminoglycans; D008744:Methylamines; D012313:RNA; D002392:Catechin; D004247:DNA; C045651:epigallocatechin gallate
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