Lipoprotein Glomerulopathy: A New Apolipoprotein E Mutation With Enhanced Glomerular Binding

Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy

“…22 ). One of these mutations, apoE Chicago (R147P), has also been found in homozygous form in an LPG patient ( 23 ). Renal transplantation led to recurrence of LPG, suggesting that renal abnormalities are not necessary for disease pathogenesis ( 24 ).…”

“…ApoE3 variants R136S, R145C, and K146E that have been linked with the development of type III hyperlipoproteinemia, have much milder repercussions on apoE3 structure and stability, indicating that although any mutation in this region of apoE3 may be detrimental to its structural and thermodynamic integrity, the strong effects described in this study may be the result of the exact amino acid substitution, more specifi cally of the introduction of the "helix-breaker" proline residue in a highly helical segment. Interestingly, the misfolding of the N-terminal domain actually enhances the kinetics of 21,23,38 ) in the pathogenesis of LPG has been previously hypothesized, but how, exactly, the mutations in the apoE protein lead to deposition of lipoproteins in the glomerulus is unknown. The nature of amino acid substitutions in these mutations, in conjunction with the structural properties of the apoE domain where they are located, prompted us to investigate the repercussions of these mutations on the protein structure and stability.…”

“…linked to LPG, namely R145P (apoE Sendai) ( 38 ), R147P (apoE Chicago) ( 23 ), and R158P (apoE Osaka or Kurashiki) ( 20,21 ) and characterized their structural, thermodynamic, and functional integrity. Our fi ndings demonstrate that the mutations induce signifi cant thermodynamic, structural, and aggregation-related perturbations in the molecule of apoE3 that induce unfolding of the N-terminal domain to a more molten-globule-like structure.…”

A Novel Mutation ApoE2 Kurashiki (R158P) in a Patient with Lipoprotein Glomerulopathy

“…, ApoE-Chicago 12) and ApoE-Guangzhou 13) . These reports hypothesize that the structural changes of apoE, induced by substitution with proline, may reduce the binding ability of LDL receptors because proline acts as a structure breaker in the mid- .…”

Significance of a Novel Apolipoprotein E Variant, ApoE Osaka/Kurashiki, in Lipoprotein Glomerulopathy

“…On the other hand, the substitution of proline for arginine was the first apoE mutation in LPG, called apoE Sendai (Arg145Pro) 4) , which comprises the majority of apoE variants related to LPG. Moreover, apoE Chicago (Arg147Pro) 8) and apoE Guangzhou (Arg150Pro) 9) have been reported in the United States and China, respectively. Proline acts as a structural disrupter in the middle of the alpha helix, and is commonly found as the first residue of the alpha helix or in turns in an amino acid arrangement 1,4) .…”