School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
School of Chemistry and Photon Science Institute, University of Manchester, Manchester, UK.
Sci Rep. 2017 Aug 22;7(1):9151. doi: 10.1038/s41598-017-09467-9.
HD-PTP is a tumour suppressor phosphatase that controls endocytosis, down-regulation of mitogenic receptors and cell migration. Central to its role is the specific recruitment of critical endosomal sorting complexes required for transport (ESCRTs). However, the molecular mechanisms that enable HD-PTP to regulate ESCRT function are unknown. We have characterised the molecular architecture of the entire ESCRT binding region of HD-PTP using small angle X-ray scattering and hydrodynamic analyses. We show that HD-PTP adopts an open and extended conformation, optimal for concomitant interactions with multiple ESCRTs, which contrasts with the compact conformation of the related ESCRT regulator Alix. We demonstrate that the HD-PTP open conformation is functionally competent for binding cellular protein partners. Our analyses rationalise the functional cooperation of HD-PTP with ESCRT-0, ESCRT-I and ESCRT-III and support a model for regulation of ESCRT function by displacement of ESCRT subunits, which is crucial in determining the fate of ubiquitinated cargo.
HD-PTP 是一种肿瘤抑制磷酸酶，可控制内吞作用、有丝分裂受体的下调和细胞迁移。其核心作用是特异性募集关键的内体分选复合物，这些复合物是运输所必需的（ESCRTs）。然而，能够使 HD-PTP 调节 ESCRT 功能的分子机制尚不清楚。我们使用小角度 X 射线散射和流体动力学分析，对 HD-PTP 的整个 ESCRT 结合区域的分子结构进行了表征。我们表明，HD-PTP 采用开放和延伸的构象，这最有利于与多个 ESCRTs 同时相互作用，这与相关的 ESCRT 调节剂 Alix 的紧凑构象形成对比。我们证明，HD-PTP 的开放构象在功能上能够与细胞蛋白伴侣结合。我们的分析使 HD-PTP 与 ESCRT-0、ESCRT-I 和 ESCRT-III 的功能合作合理化，并支持通过置换 ESCRT 亚基来调节 ESCRT 功能的模型，这对于确定泛素化货物的命运至关重要。
