Tsai Pei-Ling, Zhao Chenguang, Turner Elizabeth, Schlieker Christian
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States.
Department of Cell Biology, Yale School of Medicine, New Haven, United States.
Elife. 2016 Jun 23;5:e16011. doi: 10.7554/eLife.16011.
Lamin B receptor (LBR) is a polytopic membrane protein residing in the inner nuclear membrane in association with the nuclear lamina. We demonstrate that human LBR is essential for cholesterol synthesis. LBR mutant derivatives implicated in Greenberg skeletal dysplasia or Pelger-Huët anomaly fail to rescue the cholesterol auxotrophy of a LBR-deficient human cell line, consistent with a loss-of-function mechanism for these congenital disorders. These disease-causing variants fall into two classes: point mutations in the sterol reductase domain perturb enzymatic activity by reducing the affinity for the essential cofactor NADPH, while LBR truncations render the mutant protein metabolically unstable, leading to its rapid degradation at the inner nuclear membrane. Thus, metabolically unstable LBR variants may serve as long-sought-after model substrates enabling previously impossible investigations of poorly understood protein turnover mechanisms at the inner nuclear membrane of higher eukaryotes.
核纤层蛋白B受体（LBR）是一种多跨膜蛋白，与核纤层相关，位于内核膜中。我们证明人类LBR对胆固醇合成至关重要。与格林伯格骨骼发育不良或Pelger-Huët异常相关的LBR突变衍生物无法挽救LBR缺陷型人类细胞系的胆固醇营养缺陷，这与这些先天性疾病的功能丧失机制一致。这些致病变体分为两类：固醇还原酶结构域中的点突变通过降低对必需辅因子NADPH的亲和力来扰乱酶活性，而LBR截短则使突变蛋白代谢不稳定，导致其在内核膜处快速降解。因此，代谢不稳定的LBR变体可能是长期以来寻找的模型底物，能够对高等真核生物内核膜上理解不足的蛋白质周转机制进行以前无法进行的研究。
