title: Avoiding the oligomeric state: αB-crystallin inhibits fragmentation and induces dissociation of apolipoprotein C-II amyloid fibrils.
abstract: The in vivo aggregation of proteins into amyloid fibrils suggests that cellular mechanisms that normally prevent or reverse this aggregation have failed. The small heat-shock molecular chaperone protein αB-crystallin (αB-c) inhibits amyloid formation and colocalizes with amyloid plaques; however, the physiological reason for this localization remains unexplored. Here, using apolipoprotein C-II (apoC-II) as a model fibril-forming system, we show that αB-c binds directly to mature amyloid fibrils (Kd 5.4 ± 0.5 μM). In doing so, αB-c stabilized the fibrils from dilution-induced fragmentation, halted elongation of partially formed fibrils, and promoted the dissociation of mature fibrils into soluble monomers. Moreover, in the absence of dilution, the association of αB-c with apoC-II fibrils induced a 14-fold increase in average aggregate size, resulting in large fibrillar tangles reminiscent of protein inclusions. We propose that the binding of αB-c to fibrils prevents fragmentation and mediates the lateral association of fibrils into large inclusions. We further postulate that transient interactions of apoC-II with αB-c induce a fibril-incompetent monomeric apoC-II form, preventing oligomerization and promoting fibril dissociation. This work reveals previously unrecognized mechanisms of αB-c chaperone action in amyloid assembly and fibril dynamics, and provides a rationale for the in vivo colocalization of small heat-shock proteins with amyloid deposits.-Binger, K. J., Ecroyd, H., Yang, S., Carver, J. A., Howlett, G. J., Griffin, M. D. W. Avoiding the oligomeric state: αB-crystallin inhibits fragmentation and induces dissociation of apolipoprotein C-II amyloid fibrils.
authors.affiliation: Department of Biochemistry, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Rd., Parkville, VIC 3010, Australia.
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Binger
authors.forename: Heath
authors.initials: H
authors.lastname: Ecroyd
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: John A
authors.initials: JA
authors.lastname: Carver
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Howlett
authors.forename: Michael D W
authors.initials: MD
authors.lastname: Griffin
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053304:Apolipoprotein C-II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D055503:Protein Multimerization; D038203:alpha-Crystallin B Chain / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D053304:Apolipoprotein C-II; D038203:alpha-Crystallin B Chain