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转化生长因子β信号调节因子SARA/Endofin与HD-PTP特异性相互作用的结构基础

Structural Basis for Specific Interaction of TGFβ Signaling Regulators SARA/Endofin with HD-PTP.

作者信息

Gahloth Deepankar, Levy Colin, Walker Louise, Wunderley Lydia, Mould A Paul, Taylor Sandra, Woodman Philip, Tabernero Lydia

机构信息

School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.

School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.

出版信息

Structure. 2017 Jul 5;25(7):1011-1024.e4. doi: 10.1016/j.str.2017.05.005. Epub 2017 Jun 8.

DOI:10.1016/j.str.2017.05.005
PMID:28602823
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5501724/
Abstract

SARA and endofin are endosomal adaptor proteins that drive Smad phosphorylation by ligand-activated transforming growth factor β/bone morphogenetic protein (TGFβ/BMP) receptors. We show in this study that SARA and endofin also recruit the tumor supressor HD-PTP, a master regulator of endosomal sorting and ESCRT-dependent receptor downregulation. High-affinity interactions occur between the SARA/endofin N termini, and the conserved hydrophobic region in the HD-PTP Bro1 domain that binds CHMP4/ESCRT-III. CHMP4 engagement is a universal feature of Bro1 proteins, but SARA/endofin binding is specific to HD-PTP. Crystallographic structures of HD-PTP in complex with SARA, endofin, and three CHMP4 isoforms revealed that all ligands bind similarly to the conserved site but, critically, only SARA/endofin interact at a neighboring pocket unique to HD-PTP. The structures, together with mutagenesis and binding analysis, explain the high affinity and specific binding of SARA/endofin, and why they compete so effectively with CHMP4. Our data invoke models for how endocytic regulation of TGFβ/BMP signaling is controlled.

摘要

SARA和内吞素是内体衔接蛋白，它们通过配体激活的转化生长因子β/骨形态发生蛋白（TGFβ/BMP）受体驱动Smad磷酸化。我们在本研究中表明，SARA和内吞素还招募肿瘤抑制因子HD-PTP，它是内体分选和依赖于ESCRT的受体下调的主要调节因子。SARA/内吞素的N末端与HD-PTP的Bro1结构域中与CHMP4/ESCRT-III结合的保守疏水区域之间发生高亲和力相互作用。CHMP4结合是Bro1蛋白的普遍特征，但SARA/内吞素结合是HD-PTP特有的。HD-PTP与SARA、内吞素以及三种CHMP4异构体形成复合物的晶体结构表明，所有配体都以类似方式结合到保守位点，但关键的是，只有SARA/内吞素在HD-PTP特有的相邻口袋处相互作用。这些结构，连同诱变和结合分析，解释了SARA/内吞素的高亲和力和特异性结合，以及它们与CHMP4竞争如此有效的原因。我们的数据提出了关于TGFβ/BMP信号内吞调节如何被控制的模型。

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