Hydrophobic interactions of serpins

Detta är en avhandling från Sabina Janciauskiene, Wallenberglab, University Hospital Malmö, S-20502 Malmö, Sweden

Sammanfattning: The proteins of the serpin family are primarily but not exclusively proteinase inhibitors, which share a common, similar structure. It is known that this structure undergoes major conformational changes upon cleavage in the serpin reactive site loop, and that these changes include rearrangements within the hydrophobic core of the molecule. AAT and the free C-terminal peptide dissociated from cleaved AAT are found in human bile, where they are exposed to high concentrations of hydrophobic compounds, such as cholesterol and denaturing bile salts. ACT has been identified in the amyloid deposits of Alzheimer`s disease, where it is exposed to the hydrophobic peptide, Ab, from which neurotoxic amyloid fibrils are formed. The present studies were designed to determine the effects of such hydrophobic components on AAT and ACT. The interactions of AAT with hydrophobic bile acids and with its own hydrophobic C-terminal peptide were studied. The effects of these small molecules on the structure and biochemical properties of AAT were determined. The interaction of ACT with Ab was characterized, and the effects of ACT on fibril formation were determined. The binding of small sterol ligands in the hydrophobic core of AAT alters the conformation and aggregation properties of AAT. Large scale changes of AAT structure also occur in bile, which result in alteration of antigenicity and loss of activity of AAT. The C-terminal peptide from AAT has been found to polymerize into amyloid fibrils, which can be disrupted by intact AAT. The heterogeneous fibrils formed from the immunoglobulin lambda light chain were also found to be disaggregated by intact AAT. A specific interaction of ACT with Ab was found to be dependent on the concentrations of both interacting components and to affect the fibrillogenic property of the peptide and the heat stability and inhibitory activity of ACT. Available structural information and solution stability data enabled a model of the complex between ACT and Ab to be designed and a mechanism proposed of the action of ACT in fibril formation. Interaction of AAT and ACT with specific hydrophobic molecules and milieus results in conformational transitions of the serpin structure, with attendant changes in physicochemical properties which may be relevant to disease states.

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