Apolipoproteins and amyloid fibril formation in disease
Our recent work led to the identification of several small molecule activators and inhibitors of amyloid formation and identified new roles for small heat shock chaperone proteins in the formation and dynamics of amyloid fibrils. We believe that small molecules and chaperone proteins play hitherto unrecognised roles in protein folding and assembly with the potential to modulate aberrant protein mis-folding and disease.
Figure 1: Schematic of the interaction of the small heat shock protein, αB-crystallin, with apoC-II monomer and fibrils. Fibril assembly by apoC-II (shaded region) proceeds via a nucleation-dependent mechanism which includes the assembly of stable nuclei from fibril-competent monomers, and elongation of these nuclei to form mature fibrils. A transient interaction between αB-c and apoC-II monomer prevents fibril assembly, likely by inducing a fibril-incompetent monomeric conformation. The formation of fibril-incompetent apoC-II also induces the dissociation of monomer from fibrils. In contrast, the interaction between αB-c and mature fibrils is of higher affinity, inhibits fibril fragmentation, and induces the formation of large protein inclusions by lateral association of fibrils over extended time-periods. Here, a dimeric form of αB-c is depicted. However, the exact species that binds to the amyloid fibrils has not been identified.
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