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A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein.
PLOS Genetics ( IF 4.5 ) Pub Date : 2020-08-06 , DOI: 10.1371/journal.pgen.1008941
Meredith H Wilson 1 , Sujith Rajan 2 , Aidan Danoff 1, 3 , Richard J White 4, 5 , Monica R Hensley 1 , Vanessa H Quinlivan 1 , Rosario Recacha 6 , James H Thierer 1, 3 , Frederick J Tan 1 , Elisabeth M Busch-Nentwich 4, 5 , Lloyd Ruddock 6 , M Mahmood Hussain 2 , Steven A Farber 1, 3
Affiliation  

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.



中文翻译:

点突变解耦微粒体甘油三酯转移蛋白的脂质转移活性。

含载脂蛋白 B 的脂蛋白 (B-lps) 对于疏水性饮食和内源性脂质在脊椎动物的循环中的运输至关重要。斑马鱼胚胎在卵黄合胞体层 (YSL) 中产生大量 B-lps,将脂质从卵黄转移到生长组织。B-lp 生产的中断扰乱了蛋黄形态,很容易允许视觉识别具有改变的 B-lp 代谢的突变体。在这里,我们报告了微粒体甘油三酯转移蛋白 (Mtp) 错义突变的发现,Mtp 是 B-lp 生产所必需的蛋白质。这种保守的甘氨酸残基突变为缬氨酸(斑马鱼 G863V、人类 G865V)减少了 B-lp 的产生,并由于 YSL 中细胞质脂滴的异常积累而导致蛋黄不透明。然而,钟乳石( stl ) 突变。MTP 将脂质(包括甘油三酯和磷脂)转移到 ER 中的载脂蛋白 B 以进行 B-lp 组装。体外脂质转移试验表明,虽然两种 MTP 突变都消除了甘油三酯转移活性,但 G863V 突变蛋白意外地保留了约 80% 的磷脂转移活性。G863V mttp突变蛋白的这种残留磷脂转移活性足以支持小 B-lps 的分泌,从而防止在 mttp stl/ stl中观察到的肠道脂肪吸收不良和生长缺陷突变斑马鱼。基于最近的异二聚体人 MTP 复合物晶体结构的建模表明 G865V 突变可能会阻止甘油三酯进入脂质结合腔。总之,这些数据证明选择性抑制 MTP 甘油三酯转移活性可能是治疗血脂异常的可行治疗方法,并为药物设计提供结构洞察力。这些数据还强调了卵黄转运研究在鉴定对 B-lp 生物学至关重要的蛋白质方面的能力。

更新日期:2020-08-06
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