Valocin-containing protein (VCP) is a novel IQ motif containing GTPase activating protein 1 (IQGAP1) interacting protein.
Valocin-containing protein (VCP) is a novel IQ motif containing GTPase activating protein 1 (IQGAP1) interacting protein.
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Valocin 含蛋白 (VCP) 是一种新型 IQ 基序，含有 GTP 酶激活蛋白 1 (IQGAP1) 相互作用蛋白。
DOI：
10.1016/j.bbrc.2017.09.159
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
K.
中科院分区：
文献类型：
--
作者：
Itoh;N.;Nagai;T,; Watanabe;T.;Taki;K.;Nabeshima;N.;Kaibuchi;K.;Yamada;K.
支架蛋白在蛋白质复合物的形成中起着关键作用，并将结合伙伴组织成一个功能单元，以增强特定的信号通路。含有IQ基序的GTPase激活蛋白1 （IQGAP1）是脊柱形成的必需蛋白，其作用是支架多种信号复合物。然而，目前尚不清楚IQGAP1如何在大脑中相互作用。在本研究中，我们通过蛋白质组学方法筛选了新的iqgap1相互作用蛋白。作为一种新的与iqgap1相互作用的蛋白，我们发现含有valosin-containing protein （VCP）是包涵体肌病合并Paget病和额颞叶痴呆（IBMPFD）患者的致病基因。免疫沉淀法证实了IQGAP1与VCP的生理相互作用。IQGAP1的n端（N-half）和c端（C-half）片段都与VCP的n端区相互作用。体外培养4天（DIV4），在培养海马神经元的生长玉米、轴突轴、细胞体和树突中观察到IQGAP1和VCP的共定位。在DIV14培养的神经元中，IQGAP1在树突中与VCP共定位。当HEK293T细胞共转染IQGAP1和VCP时，免疫沉淀实验显示，与野生型（WT） VCP相比，IQGAP1与疾病相关突变体（R155H或A232E） VCP的结合明显减少。这些结果表明，IQGAP1和VCP相互作用的减少可能与IBMPFD的病理生理有关。
Scaffold proteins play a pivotal role in making protein complexes, and organize binding partners into a functional unit to enhance specific signaling pathways. IQ motif-containing GTPase activating protein 1 (IQGAP1) is an essential protein for spine formation due to its role in scaffolding multiple signal complexes. However, it remains unclear how IQGAP1 interacts within the brain. In the present study, we screened novel IQGAP1-interacting proteins by a proteomic approach. As a novel IQGAP1-interacting protein, we identified valosin-containing protein (VCP) which is a causative gene in patients with inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). The physiological interaction of IQGAP1 with VCP was confirmed by an immunoprecipitation assay. Both the N-terminal (N-half) and C-terminal (C-half) fragments of IQGAP1 interacted with the N-terminal region of VCP. Co-localization of IQGAP1 and VCP was observed in the growth corn, axonal shaft, cell body, and dendrites in cultured hippocampal neurons at 4 daysin vitro(DIV4). In cultured neurons at DIV14, IQGAP1 co-localized with VCP in dendrites. When HEK293T cells were co-transfected with IQGAP1 and VCP, an immunoprecipitation assay revealed that binding of IQGAP1 with disease-related mutant (R155H or A232E) VCP was markedly reduced compared to wild-type (WT) VCP. These results suggest that reduction of IQGAP1 and VCP interaction may be associated with the pathophysiology of IBMPFD.