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Thermodynamic destabilization and aggregation propensity as the underlying mechanism behind the genetic association of apoE3 mutants and Lipoprotein Glomerulopathy.
Journal of Lipid Research 2018 October 12
Lipoprotein glomerulopathy (LPG) is a rare renal disease, characterized by lipoprotein thrombi in glomerular capillaries. A series of apolipoprotein E (apoE) mutations have been associated with LPG development. We previously showed that three mutants based on apoE3 sequence, in which an arginine was substituted by proline, are thermodynamically destabilized and aggregation-prone. To examine whether other LPG-associated apoE3 mutations induce similar effects, we characterized three non-proline LPG-associated apoE3 mutations, namely the R25C (apoEKyoto), R114C (apoETsukuba) and A152D (apoELasVegas). All three apoE3 variants are found to have significantly reduced helical content and to be thermodynamically destabilized, both in lipid-free and lipoprotein-associated form, and to expose a larger portion of hydrophobic surface to the solvent compared to wild-type apoE3. Furthermore, all three apoE3 variants are aggregation-prone as shown by dynamic light-scattering measurements and by their enhanced capacity to bind the amyloid probe thioflavin T. Overall, our data suggest that the LPG-associated apoE3 mutations R25C, R114C and A152D induce protein misfolding which may contribute to protein aggregation in glomerular capillaries. The similar effects of both LPG-associated proline and non-proline mutations on apoE3 structure suggest that the thermodynamic destabilization and enhanced aggregation of apoE3 may constitute a common underlying mechanism behind the pathogenesis of LPG.
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