Structural characterization of the C‐terminal coiled‐coil domains of wild‐type and kidney disease‐associated mutants of apolipoprotein L1. (1st April 2016) - Sharma, Alok K.
Abstract : Trypanosomes that cause sleeping sickness endocytose apolipoprotein L1 (APOL1)‐containing trypanolytic factors from human serum, leading to trypanolytic death through generation of APOL1‐associated lytic pores in trypanosomal membranes. The trypanosome Trypanosoma brucei rhodesiense counteracts trypanolysis by expressing the surface protein serum response‐associated (SRA), which can bind APOL1 common variant G0 to block its trypanolytic activity. However, two missense variants in the C terminal predicted coiled‐coil (CC) domains of human APOL1 G1 (S342G/I384M) and G2 (ΔN388Y389) decrease or abrogate APOL1 binding to T. brucei rhodesiense SRA, thus preserving APOL1 trypanolytic activity. These evolutionarily selected APOL1 missense variants, found at a high frequency in some populations of African descent, also confer elevated risk of kidney disease. Understanding the SRA–APOL1 interaction and the role of APOL1 G1 and G2 variants in kidney disease demands structural characterization of the APOL1 CC domain. Using CD, heteronuclear NMR, and molecular dynamics (MD) simulation on structural homology models, we report here unique and dynamic solution conformations of nephropathy variants G1 and G2 as compared with the common variant G0. Conformational plasticity in G1 and G2 CC domains led to interhelical α1–α2 approximation coupled with secondary structural changes and delimited motional properties absent in the G0 CC domain. The G1 substitutions conferred local structural changes principally along helix α1, whereas the G2 deletion altered the structure of both helix α2 and helix α1. These dynamic features of APOL1 CC variants likely reflect their intrinsic structural properties, and should help interpret future APOL1 structural studies and define the contribution of APOL1 risk variants to kidney disease. Abstract : The C‐terminal predicted coiled coil (CC) domain of human trypanolytic APOL1 is the site of kidney disease‐associated polymorphic variants G1 (S342G/I384M) and G2 (ΔN388/Y389). Experimental and computational MD simulation approaches reveal substantial structural differences between the CC domain of common variant G0 and the CC domains of G1 and G2, as shown in the figure.