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Abstract: FR-PO920

Nuclear Magnetic Resonance Studies Reveal Structural Differences Between APOL1 G0 and G1 C-Terminus

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Madhavan, Sethu M., The Ohio State University, Columbus, Ohio, United States
  • Hansen, Alexandar L., The Ohio State University, Columbus, Ohio, United States
  • Cao, Shufen, Case Western Reserve University, Cleveland, Ohio, United States
  • Sedor, John R., Cleveland Clinic, Cleveland, Ohio, United States

Common variants (G1: S342G and I384M, G2: N388del and Y389del) located in the C-terminus of APOL1 associate with high risk of progression to end stage kidney disease. Our previous studies using molecular modeling suggested that APOL1 C-terminus adopts an alpha-helical structure and G1 and G2 variants disrupt the structural integrity of the C-terminus leading to impaired intracellular protein interactions. We used nuclear magnetic resonance (NMR) spectroscopy to experimentally characterize the structural consequence of kidney disease-associated variants.


15N and 13C isotope labeled C-terminus of APOL1-G0 and -G1 (aa 305-398) recombinant protein was generated using bacterial expression followed by metal affinity and size exclusion chromatography. The chemical shifts of backbone atoms in dodecylphosphocholine (DPC) micelles were determined by solution nuclear magnetic resonance (NMR).


Two-dimensional solution NMR studies (1H-15N-HSQC spectra) demonstrated significant differences between reference protein G0 and G1 variant chemical shits suggesting variation in protein structure. The secondary structure determined using chemical shifts of backbone atoms demonstrated helical properties of APOL1 G0 and G1 C-terminus. G1 variant interrupted the alpha-helix of APOL1 C-terminus.


The changes in the structure of APOL1 C-terminus induced by kidney disease associated variants could disrupt protein interactions and underlie the intracellular mechanisms that mediate the pathogenesis of chronic kidney disease. Further characterization of the three-dimensional protein structure and dynamics using NMR and Molecular Dynamics simulations will refine the time-dependent behavior of APOL1 variants.


  • NIDDK Support