Sharma Alok K, Friedman David J, Pollak Martin R, Alper Seth L
Nephrology Division, Harvard Medical School, Boston, MA, USA.
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
FEBS J. 2016 May;283(10):1846-62. doi: 10.1111/febs.13706. Epub 2016 Apr 1.
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.
引发昏睡病的锥虫会从人血清中内吞含载脂蛋白L1（APOL1）的溶锥虫因子，通过在锥虫细胞膜上生成与APOL1相关的裂解孔导致锥虫溶解死亡。布氏罗得西亚锥虫通过表达表面蛋白血清反应相关蛋白（SRA）来对抗锥虫溶解，该蛋白可结合APOL1常见变体G0以阻断其溶锥虫活性。然而，人APOL1 G1（S342G/I384M）和G2（ΔN388Y389）的C末端预测卷曲螺旋（CC）结构域中的两个错义变体降低或消除了APOL1与布氏罗得西亚锥虫SRA的结合，从而保留了APOL1的溶锥虫活性。这些在非洲裔某些人群中高频出现的经进化选择的APOL1错义变体，也会增加患肾病的风险。了解SRA-APOL1相互作用以及APOL1 G1和G2变体在肾病中的作用需要对APOL1 CC结构域进行结构表征。通过对结构同源模型进行圆二色光谱（CD）、异核核磁共振（NMR）和分子动力学（MD）模拟，我们在此报告了与常见变体G0相比，肾病变体G1和G2独特且动态的溶液构象。G1和G2 CC结构域中的构象可塑性导致α1-α2螺旋间近似，同时伴有二级结构变化以及G0 CC结构域中不存在的有限运动特性。G1替换主要沿α1螺旋导致局部结构变化，而G2缺失则改变了α2螺旋和α1螺旋的结构。APOL1 CC变体的这些动态特征可能反映了它们的内在结构特性，有助于解释未来的APOL1结构研究，并确定APOL1风险变体对肾病的影响。
