HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2
HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2
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DOI：
10.1074/jbc.c100401200
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发表时间：
2001-10-19
影响因子：
4.8
通讯作者：
Hayden, MR
中科院分区：
文献类型：
--
作者：
Metzler, M;Legendre-Guillemin, V;Hayden, MR
亨廷顿蛋白中的多聚谷氨酰胺扩增是导致亨廷顿病神经变性的潜在突变。这种突变影响亨廷顿蛋白与不同蛋白质的相互作用，包括亨廷顿蛋白相互作用蛋白I（HIP（）），其中与突变亨廷顿蛋白结合的亲和力大大降低。在这里，我们证明了HIP（与神经元细胞中网格蛋白介导的内吞作用的标记物共定位，并在从脑匀浆中纯化的网格蛋白包被的囊泡（CCV）上高度富集。HIP（主要通过包含氨基酸276-335的小片段结合网格蛋白衔接蛋白2（AP 2）和网格蛋白重链的末端结构域。该区域含有共有网格蛋白和AP 2结合位点，与卷曲螺旋结构域一起发挥作用，靶向HIP（至CCV）。各种HIP 1片段的表达导致网格蛋白介导的内吞作用的有效阻断。我们的研究结果表明，HIP 1是一个新的组成部分的内吞机制。
Polyglutamine expansion in huntingtin is the underlying mutation leading to neurodegeneration in Huntington disease. This mutation influences the interaction of huntingtin with different proteins, including huntingtin-interacting protein I (HIP(), in which affinity to bind to mutant huntingtin is profoundly reduced. Here we demonstrate that HIP( colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP( binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276-335. This region, which contains consensus clathrin- and AP2-binding sites, functions in conjunction with the coiled-coil domain to target HIP( to CCVs. Expression of various HIP1 fragments leads to a potent block of clathrin-mediated endocytosis. Our findings demonstrate that HIP1 is a novel component of the endocytic machinery.