Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1.
Structural Basis for Selective Interaction between the ESCRT Regulator HD-PTP and UBAP1.
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DOI：
10.1016/j.str.2016.10.006
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发表时间：
2016-12-06
期刊：
影响因子：
5.7
通讯作者：
Tabernero, Lydia
中科院分区：
文献类型：
--
作者：
Gahloth, Deepankar;Levy, Colin;Heaven, Graham;Stefani, Flavia;Wunderley, Lydia;Mould, Paul;Cliff, Matthew J.;Bella, Jordi;Fielding, Alistair J.;Woodman, Philip;Tabernero, Lydia
转运所需的内体分选复合体(ESCRT)对于泛素依赖的有丝分裂受体的降解是必不可少的，这一过程在癌症病理学中经常受到影响。通过ESCRT对泛素受体的分类是由肿瘤抑制因子磷酸酶HD-PTP控制的。HD-PTP和ESCRT-I亚单位UBAP1之间的特异性相互作用对生长因子受体和整合素的降解至关重要。在这里，我们用X射线结晶学和双电子-电子共振谱对HD-PTP及其与UBAP1的络合物进行了结构表征。螺旋线圈结构域采用了意想不到的开放和刚性构象，这与相关ESCRT调节器Alix的闭合和灵活的螺旋线圈结构域形成了对比。HD-PTP：UBAP1结构识别了相互作用的分子决定因素，并为HD-PTP和UBAP1之间的特定功能合作提供了分子基础。我们的发现为ESCRT通路调控的分子机制提供了见解，这些机制可能与抗癌治疗相关。HD-PTP磷酸酶卷曲结构域与UBAP1的晶体结构HD-PTP的开放和刚性结构对于功能识别构象和结构决定因素在Bro1蛋白Gahloth，Levy等人中定义了选择性。目前的晶体结构的卷曲结构的HD-PTP磷酸酶，依赖ESCRT的排序调节因子，及其与ESCRT-I亚单位UBAP1的复合体。该结构揭示了一个开放的架构，对特定的相互作用至关重要，并提供了对HD-PTP如何调节有丝分裂原受体分类的见解。
Endosomal sorting complexes required for transport (ESCRTs) are essential for ubiquitin-dependent degradation of mitogenic receptors, a process often compromised in cancer pathologies. Sorting of ubiquinated receptors via ESCRTs is controlled by the tumor suppressor phosphatase HD-PTP. The specific interaction between HD-PTP and the ESCRT-I subunit UBAP1 is critical for degradation of growth factor receptors and integrins. Here, we present the structural characterization by X-ray crystallography and double electron-electron resonance spectroscopy of the coiled-coil domain of HD-PTP and its complex with UBAP1. The coiled-coil domain adopts an unexpected open and rigid conformation that contrasts with the closed and flexible coiled-coil domain of the related ESCRT regulator Alix. The HD-PTP:UBAP1 structure identifies the molecular determinants of the interaction and provides a molecular basis for the specific functional cooperation between HD-PTP and UBAP1. Our findings provide insights into the molecular mechanisms of regulation of ESCRT pathways that could be relevant to anticancer therapies. Crystal structure of the coiled-coil domain of HD-PTP phosphatase with UBAP1 The open and rigid architecture of HD-PTP is essential for functional recognition Conformation and structural determinants define selectivity in Bro1 proteins Gahloth, Levy et al. present crystal structures of the coiled-coil domain of the HD-PTP phosphatase, a regulator of ESCRT-dependent sorting, and its complex with the ESCRT-I subunit UBAP1. The structure reveals an open architecture critical for specific interactions and provides insights into how HD-PTP regulates mitogenic receptor sorting.
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DOI：
10.1016/j.str.2009.04.007
发表时间：
2009-06-10
期刊：
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影响因子：
--
作者：
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发表时间：
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期刊：
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