A human infertility-associated KASH5 variant promotes mitochondrial localization.
A human infertility-associated KASH5 variant promotes mitochondrial localization.
复制标题
人类不育相关的 KASH5 变异促进线粒体定位。
DOI：
10.1038/s41598-021-89439-2
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发表时间：
2021-05-12
影响因子：
4.6
通讯作者：
Horn HF
中科院分区：
文献类型：
--
作者：
Bentebbal SA;Meqbel BR;Salter A;Allan V;Burke B;Horn HF
KASH5是最近发现的尾锚定、外核膜（ONM）和内质网（ER）蛋白的KASH结构域家族成员。在减数分裂前期I， KASH5和SUN1形成一个跨越核膜的复合体，将减数分裂染色体的端粒与细胞质动力蛋白连接起来。这种连接对于同源染色体动力学和配对是必不可少的。最近的一项研究发现，人类KASH5 （L535Q）的一种变异与无精子症相关的男性不育有关。然而，没有描述分子机制。在这里，我们报告了在KASH5跨膜结构域（TMD）内的这种氨基酸取代对二级结构没有预测的影响。然而，根据GES （Goldman-Engelman-Steitz）氨基酸疏水性量表，计算出L535Q TMD的总体疏水性低于野生型KASH5。这种疏水性的改变深刻地影响了KASH5的亚细胞定位。通过一系列的氨基酸取代研究，我们发现L535Q取代会干扰KASH5在ER和ONM上的定位，从而导致错误靶向线粒体膜。我们认为这种定位错误解释了患者的不孕症和无精子症表型。
KASH5 is the most recently identified member of the KASH domain family of tail anchored, outer nuclear membrane (ONM) and endoplasmic reticulum (ER) proteins. During meiosis prophase I, KASH5 and SUN1 form a complex that spans the nuclear envelope and which links the telomeres of meiotic chromosomes to cytoplasmic dynein. This connection is essential for homologous chromosome dynamics and pairing. A recent study identified a variant in human KASH5 (L535Q) that correlated with male infertility associated with azoospermia. However, no molecular mechanism was described. Here, we report that this amino acid substitution, within the KASH5 transmembrane domain (TMD) has no predicted effects on secondary structure. However, the overall hydrophobicity of the L535Q TMD, is calculated to be lower than the wild-type KASH5, based on the GES (Goldman–Engelman–Steitz) amino acid hydrophobicity scale. This change in hydrophobicity profoundly affects the subcellular localization of KASH5. Through a series of amino acid substitution studies, we show that the L535Q substitution perturbs KASH5 localization to the ER and ONM and instead results in mistargeting to the mitochondria membrane. We suggest that this mislocalization accounts for the infertility and azoospermia phenotype in patients.
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影响因子：
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