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Kidney Week

Abstract: SA-OR30

Re-Envisioning the APOL1 Cation Channel Structure

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Thomson, Russell P., Hunter College, New York, New York, United States
  • Schaub, Charles Michael, City University of New York, The Graduate Center, New York, New York, United States
  • Lee, Penny, Hunter College, New York, New York, United States
  • Terra, Nada, Hunter College, New York, New York, United States
  • Raper, Jayne, Hunter College, New York, New York, United States

Apolipoprotein L-I (APOL1) is a channel forming protein that protects humans and other primates from African trypanosome infection. African Americans have inherited common APOL1 variants with increased trypanolytic potential; however, these variants are responsible for an increased risk of kidney disease compared with other variants. Human APOL1 forms non-selective cation channels in a strictly pH dependent manner: channel formation requires acidic pH, whereas channel opening requires pH neutralization. Current APOL1 structural models rely on tenuous comparisons with unrelated channel forming proteins. Here we introduce a new model of APOL1 channel structure and topology based on functional characterization of divergent APOL1 orthologs and interspecies chimeras in a planar lipid bilayer system.


We tested interspecies APOL1 chimeras and point mutations in planar lipid bilayers to identify molecular determinants of pH dependence and ion selectivity.


Strikingly, we demonstrate that cation conductance depends on the C-terminal domain, rather than the N-terminal region as previously suggested, with both pH gating and selectivity functions largely governed by a single residue - aspartate-348. Dual substitution of Asp-348 and nearby glutamate-355 eliminated pH gating, with tyrosine-351 having a steric influence. Acidic residues within a putative hairpin region (residues 177-228) affected the pH-dependence of channel formation.


Based on these data we present a radically updated domain structure of APOL1, including a putative 4-pass transmembrane topology and a pore-lining helix near the C-terminus (see Image abstract). We propose a mechanism of channel gating based on dual proton-sensing residues (Asp-348 and Glu-355) within the pore-lining helix, with Asp-348 also determining selectivity for cations over anions.

(A) Domain structure. (B) Topology model and pore-lining helix. (C) Model of the pore. Two APOL1 subunits (S1 and S2) are brought into apposition via the C-terminal leucine zipper domain.


  • Other U.S. Government Support