Amyloid fibril formation, structure and domain swapping of acyl-coenzyme A thioesterase-7

Acyl-coenzyme A thioesterase (Acot) enzymes are involved in a broad range of essential intracellular roles including cell signalling, lipid metabolism, inflammation and the opening of ion channels. Dysregulation in lipid metabolism has been linked to neuroinflammatory and neurological disorders such as Alzheimer's and Parkinson's diseases. Structurally, Acot enzymes adopt a circularised trimeric arrangement with each monomer containing an N- and a C-terminal hotdog domain. Acot7 spontaneously forms amyloid fibrils in vitro under physiological conditions. The resultant amyloid fibrillar structures were characterised by dye-binding fluorescence assays, far-UV circular dichroism spectroscopy, transmission electron microscopy and X-ray fibre diffraction. Acot7 has an unusual mechanism of aggregation with no lag phase. The initial phase (similar to 18 h) of aggregation involves conformational rearrangement within the oligomers to form species of enhanced beta-sheet character. The subsequent loss of alpha-helical structure is accompanied by large-scale amyloid fibril formation. The crystal structure of Acot7 revealed an unexpected arrangement of the two domains within the circularised trimeric structure, which is the basis for a proposed mechanism of amyloid fibril formation involving domain swapping during the initial phase of aggregation. Acot7 formed fibrils in the presence of its substrate arachidonoyl-CoA and its inhibitors and maintained its enzyme activity during fibril assembly. It is proposed that the Acot7 fibrillar form acts as functional amyloid.

Automated summary

Acot enzymes play important roles in cell signaling, lipid metabolism, inflammation, and ion channel opening. Acot7 can spontaneously form amyloid fibrils under physiological conditions. The aggregation mechanism of Acot7 involves conformational rearrangement and the formation of enhanced beta-sheet structures in the initial phase, followed by the formation of amyloid fibrils.