Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
EMBO J. 2011 May 13;30(12):2490-500. doi: 10.1038/emboj.2011.147.
Dolichol monophosphate (Dol-P) functions as an obligate glycosyl carrier lipid in protein glycosylation reactions. Dol-P is synthesized by the successive condensation of isopentenyl diphosphate (IPP), with farnesyl diphosphate catalysed by a cis-isoprenyltransferase (cis-IPTase) activity. Despite the recognition of cis-IPTase activity 40 years ago and the molecular cloning of the human cDNA encoding the mammalian enzyme, the molecular machinery responsible for regulating this activity remains incompletely understood. Here, we identify Nogo-B receptor (NgBR) as an essential component of the Dol-P biosynthetic machinery. Loss of NgBR results in a robust deficit in cis-IPTase activity and Dol-P production, leading to diminished levels of dolichol-linked oligosaccharides and a broad reduction in protein N-glycosylation. NgBR interacts with the previously identified cis-IPTase hCIT, enhances hCIT protein stability, and promotes Dol-P production. Identification of NgBR as a component of the cis-IPTase machinery yields insights into the regulation of dolichol biosynthesis.
二磷酸多萜醇（Dol-P）在蛋白质糖基化反应中作为必需的糖基载体脂质发挥作用。Dol-P 通过异戊烯二磷酸（IPP）的连续缩合合成，由顺式异戊烯基转移酶（cis-IPTase）活性催化法尼基二磷酸（Farnesyl diphosphate）。尽管 cis-IPTase 活性在 40 年前被识别，并且编码哺乳动物酶的人 cDNA 被分子克隆，但负责调节这种活性的分子机制仍不完全了解。在这里，我们将神经生长抑制因子-B 受体（NgBR）鉴定为 Dol-P 生物合成机制的重要组成部分。NgBR 的缺失导致 cis-IPTase 活性和 Dol-P 产生的强烈缺陷，导致 Dol-P 连接寡糖的水平降低，以及蛋白质 N-糖基化的广泛减少。NgBR 与先前鉴定的 cis-IPTase hCIT 相互作用，增强 hCIT 蛋白稳定性，并促进 Dol-P 产生。将 NgBR 鉴定为 cis-IPTase 机制的组成部分，为 Dol-P 生物合成的调节提供了新的见解。
