Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs
Mutations in Disordered Regions Can Cause Disease by Creating Dileucine Motifs
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DOI：
10.1016/j.cell.2018.08.019
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发表时间：
2018-09-20
期刊：
影响因子：
64.5
通讯作者：
Selbach, Matthias
中科院分区：
文献类型：
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作者：
Meyer, Katrina;Kirchner, Marieluise;Selbach, Matthias
许多致病的错义突变影响蛋白质的内在无序区（IDR），但其致病的分子机制是谜。在这里，我们采用基于肽的蛋白质组学筛选，以研究IDR突变对蛋白质-蛋白质相互作用的影响。我们发现，在三个跨膜蛋白（GLUT 1，ITPR 1，和CACNA 1H）的无序胞质区域的突变导致网格蛋白结合增加。所有这三种突变都产生了已知介导网格蛋白依赖性运输的双亮氨酸基序。对GLUT 1（SLC 2A 1）（GLUT 1缺乏综合征的葡萄糖转运蛋白）的后续实验表明，突变的蛋白质错误定位于细胞内区室。突变体GLUT 1在体外与衔接蛋白（AP）相互作用，敲低AP-2可逆转细胞错误定位，恢复葡萄糖转运。对其他已知致病变体的系统分析揭示了在跨膜蛋白的结构紊乱的胞质结构域中获得的双亮氨酸基序的显著和特异性的过度表达。因此，在无序区域的几个突变似乎引起“双亮氨酸病”。''
Many disease-causing missense mutations affect intrinsically disordered regions (IDRs) of proteins, but the molecular mechanism of their pathogenicity is enigmatic. Here, we employ a peptide-based proteomic screen to investigate the impact of mutations in IDRs on protein-protein interactions. We find that mutations in disordered cytosolic regions of three transmembrane proteins (GLUT1, ITPR1, and CACNA1H) lead to an increased clathrin binding. All three mutations create dileucine motifs known to mediate clathrin-dependent trafficking. Follow-up experiments on GLUT1 (SLC2A1), the glucose transporter causative of GLUT1 deficiency syndrome, revealed that the mutated protein mislocalizes to intracellular compartments. Mutant GLUT1 interacts with adaptor proteins (APs) in vitro, and knocking down AP-2 reverts the cellular mislocalization and restores glucose transport. A systematic analysis of other known disease-causing variants revealed a significant and specific overrepresentation of gained dileucine motifs in structurally disordered cytosolic domains of transmembrane proteins. Thus, several mutations in disordered regions appear to cause "dileucineopathies.''