Kidney-disease-associated variants of Apolipoprotein L1 show gain of function in cation channel activity
| Autor: | Jonathan Bruno, John C. Edwards |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
chloride channel Cell Membrane Permeability Apolipoprotein B Apolipoprotein L1 ApoL1 Val valinomycin Kidney Biochemistry chemistry.chemical_compound Voltage-Dependent Anion Channels Protein–lipid interaction DDM n-dodecyl-β-D-maltoside biology Chemistry Gain of Function Mutation Chloride channel Kidney Diseases Lipoproteins HDL Cation channel activity Research Article potassium channel protein–lipid interaction Signal Transduction Gene isoform PVDF polyvinylidene fluoride Phospholipid apolipoprotein Black People 03 medical and health sciences phospholipid vesicle Cations Humans Genetic Predisposition to Disease Molecular Biology Ion channel Ion Transport 030102 biochemistry & molecular biology Cell Membrane cation channel ApoL1 apolipoprotein L1 Biological Transport Cell Biology CI1 chloride ionophore 1 FSGS 030104 developmental biology ion channel biology.protein SD standard deviation |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Variants in Apolipoprotein L1 (ApoL1) are known to be responsible for increased risk of some progressive kidney diseases among people of African ancestry. ApoL1 is an amphitropic protein that can insert into phospholipid membranes and confer anion- or cation-selective permeability to phospholipid membranes depending on pH. Whether these activities differ among the variants or whether they contribute to disease pathogenesis is unknown. We used assays of voltage-driven ion flux from phospholipid vesicles and of stable membrane association to assess differences among ApoL1 isoforms. There is a significant (approximately twofold) increase in the cation-selective ion permease activity of the two kidney-disease-associated variants compared with the reference protein. In contrast, we find no difference in the anion-selective permease activity at low pH among the isoforms. Compared with the reference sequence, the two disease-associated variants show increased stable association with phospholipid vesicles under conditions that support the cation permease activity, suggesting that the increased activity may be due to more efficient membrane association and insertion. There is no difference in membrane association among isoforms under optimal conditions for the anion permease activity. These data support a model in which enhanced cation permeability may contribute to the progressive kidney diseases associated with high-risk ApoL1 alleles. |
| Databáze: | OpenAIRE |
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