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Structural characterization of the C‐terminal coiled‐coil domains of wild‐type and kidney disease‐associated mutants of apolipoprotein L1
Author(s) -
Sharma Alok K.,
Friedman David J.,
Pollak Martin R.,
Alper Seth L.
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13706
Subject(s) - missense mutation , biology , mutant , homology modeling , coiled coil , structural motif , trypanosoma brucei , genetics , chemistry , mutation , biophysics , biochemistry , gene , enzyme
Trypanosomes that cause sleeping sickness endocytose apolipoprotein L1 ( APOL 1)‐containing trypanolytic factors from human serum, leading to trypanolytic death through generation of APOL 1‐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 APOL 1 common variant G0 to block its trypanolytic activity. However, two missense variants in the C terminal predicted coiled‐coil ( CC ) domains of human APOL 1 G1 (S342G/I384M) and G2 (ΔN388Y389) decrease or abrogate APOL 1 binding to T. brucei rhodesiense SRA , thus preserving APOL 1 trypanolytic activity. These evolutionarily selected APOL 1 missense variants, found at a high frequency in some populations of African descent, also confer elevated risk of kidney disease. Understanding the SRA – APOL 1 interaction and the role of APOL 1 G1 and G2 variants in kidney disease demands structural characterization of the APOL 1 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 APOL 1 CC variants likely reflect their intrinsic structural properties, and should help interpret future APOL 1 structural studies and define the contribution of APOL 1 risk variants to kidney disease.