Avoiding the oligomeric state: αB‐crystallin inhibits fragmentation and induces dissociation of apolipoprotein C‐II amyloid fibrils. Issue 3 (16th November 2012)

• Record Type: Journal Article
• Authors: Binger, Katrina J.; Ecroyd, Heath; Yang, Shuo; Carver, John A.; Howlett, Geoffrey J.; Griffin, Michael D. W.
• Is Part Of: FASEB journal. Volume 27:Issue 3(2013)
• Page Start: 1214
• Page End: 1222
• Publication Date: 2012-11-16
• Subjects: protein misfolding -- aggregation -- molecular chaperone -- heat‐shock protein; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.12-220657
• Languages: English
• ISSNs: 0892-6638

Abstract

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. FASEB J. 27, 1214–1222 (2013). www.fasebj.org