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

ABSTRACT: Lipoprotein glomerulopathy (LPG) is a dominant inherited kidney disorder characterized by lipoprotein thrombi in glomerular capillaries. Single-amino-acid mutations in apoE have been associated with the development of the disease, although the mechanism is unknown. In an effort to gain mechanistic insight linking the presence of such mutations and the development of LPG, we evaluated the effects of three of the most common apoE3 variants associated with this disease, namely R145P(Sendai), R147P(Chicago), and R158P(Osaka or Kurashiki), on the structural and conformational integrity of the protein. All three variants were found to have significantly reduced helical content, to expose a larger portion of hydrophobic surface to the solvent, and to be significantly thermodynamically destabilized, often lacking functionally relevant unfolding intermediates. Furthermore, all variants were aggregation prone and had enhanced sensitivity to protease digestion. Finally, although the variants were able to form discoidal lipoprotein particles, discrete subpopulations of poorly formed or aberrant particles were evident. Furthermore, these lipoprotein particles were thermodynamically destabilized and aggregation prone. Overall, our data suggest that these mutations induce a generalized unfolding of the N-terminal domain of apoE3 toward a molten-globule-like structure. ApoE3 N-terminal domain unfolding due to mutation may constitute a common mechanism underlying the protein's association with the pathogenesis of LPG.

SUBMITTER: Georgiadou D

PROVIDER: S-EPMC3520522 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Georgiadou Dimitra D Stamatakis Kostas K Efthimiadou Eleni K EK Kordas George G Gantz Donald D Chroni Angeliki A Stratikos Efstratios E

Journal of lipid research 20121030 1

Lipoprotein glomerulopathy (LPG) is a dominant inherited kidney disorder characterized by lipoprotein thrombi in glomerular capillaries. Single-amino-acid mutations in apoE have been associated with the development of the disease, although the mechanism is unknown. In an effort to gain mechanistic insight linking the presence of such mutations and the development of LPG, we evaluated the effects of three of the most common apoE3 variants associated with this disease, namely R145P(Sendai), R147P( ...[more]

PMID: 23110818

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Project description:BackgroundLipoprotein glomerulopathy (LPG) is a rare autosomal dominant kidney disease that is most commonly caused by mutations in ApoE Kyoto (p.R43C) and ApoE Sendai (p.R163P). Differences in phenotype among the various ApoE mutations have been suggested, but the pathogenic role of ApoE Kyoto has not been validated in an animal model. This study intended to establish an ApoE Kyoto murine model and to further compare the pathologic differences between ApoE Kyoto and ApoE Sendai.MethodMale ApoE-deficient mice, 3 months of age, were divided into five groups, including the AD-ApoE Sendai, AD-ApoE Kyoto, AD-ApoE3, AD-eGFP, and ApoE (-/-) groups. The first four groups received recombinant adenovirus that contained the entire coding regions of the human ApoE Sendai and ApoE Kyoto, apoE3, and eGFP genes, respectively. Fasting blood and urine samples were collected at multiple time points. Lipid profiles and urine albumin-creatinine ratio were measured. Renal and aortic histopathologic alterations were analyzed.ResultsAfter virus injection, plasma human ApoE was detected and rapidly reached the maximum level at 4-6 days in the AD-ApoE Kyoto and AD-ApoE Sendai groups (17.4 ± 3.1 µg/mL vs.: 22.2 ± 4.5 µg/mL, respectively) and at 2 days in the AD-ApoE3 group (38.4 µg/mL). The serum total cholesterol decreased by 63%, 65%, and 73% in the AD-ApoE Kyoto, AD-ApoE Sendai and AD-ApoE3 groups, respectively. There were no significant changes in serum triglyceride and urinary albumin-creatinine ratio among the five groups. Typical lipoprotein thrombi with positive ApoE staining were detected in the AD-ApoE Kyoto and AD-ApoE Sendai groups. The Oil-red O-positive glomerular area tended to be higher in the AD-ApoE Kyoto group (9.2%) than in the AD-ApoE Sendai (3.9%), AD-ApoE3 (4.8%), AD-eGFP (2.9%), and ApoE (-/-) (3.6%) groups. The atherosclerotic plaque area in the aorta was lower in the group injected with various ApoE mutations than in the group without injection of ApoE mutation.ConclusionsIn this animal study, we first established an ApoE Kyoto mutation murine model and confirmed its pathogenic role in LPG. Our results suggested that LPG may be more severe with the ApoE Kyoto than with the ApoE Sendai.

Dataset Information

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

Publications

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

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