Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor.
Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor.
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DOI：
10.1083/jcb.201711047
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发表时间：
2018-05-07
期刊：
影响因子：
--
通讯作者：
Coskun Ü
中科院分区：
文献类型：
--
作者：
Gutmann T;Kim KH;Grzybek M;Walz T;Coskun Ü
Gutmann等人利用重组成纳米盘的人胰岛素受体的单粒子电子显微镜，表明配体结合诱导受体外畴的构象重排，导致跨膜结构域的二聚化和受体激活。胰岛素受体（IR）信号在多细胞生物的代谢和生长调控中起着至关重要的作用。IRs在受体酪氨酸激酶中是独一无二的，因为它们仅以共价（αβ）2同二聚体的形式存在于细胞表面。因此，IR的跨膜信号传导不能基于配体诱导的二聚体，而必须涉及现有受体二聚体的结构变化。在这项研究中，我们使用糖基化的全长人IR重组成脂质纳米盘，通过单粒子电子显微镜显示胰岛素与二聚体受体的结合将其外结构域从倒u形构象转化为t形构象。胞外结构域的这种结构重排扩展到跨膜结构域，这些结构域在非活性构象中分离得很好，但在胰岛素结合时靠近在一起，促进细胞质激酶结构域的自磷酸化。
Using single-particle electron microscopy of the human insulin receptor reconstituted into nanosdiscs, Gutmann et al. show that ligand binding induces a conformational rearrangement in the receptor ectodomain that results in the dimerization of the transmembrane domains and receptor activation. Insulin receptor (IR) signaling plays a critical role in the regulation of metabolism and growth in multicellular organisms. IRs are unique among receptor tyrosine kinases in that they exist exclusively as covalent (αβ)2 homodimers at the cell surface. Transmembrane signaling by the IR can therefore not be based on ligand-induced dimerization as such but must involve structural changes within the existing receptor dimer. In this study, using glycosylated full-length human IR reconstituted into lipid nanodiscs, we show by single-particle electron microscopy that insulin binding to the dimeric receptor converts its ectodomain from an inverted U-shaped conformation to a T-shaped conformation. This structural rearrangement of the ectodomain propagates to the transmembrane domains, which are well separated in the inactive conformation but come close together upon insulin binding, facilitating autophosphorylation of the cytoplasmic kinase domains.
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影响因子：
16.6
作者：
Freed, Daniel M.;Alvarado, Diego;Lemmon, Mark A.
通讯作者：
Lemmon, Mark A.
DOI：
10.1038/nrm.2017.89
发表时间：
2018-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Haeusler RA;McGraw TE;Accili D
通讯作者：
Accili D
影响因子：
3
作者：
Hohn, Michael;Tang, Grant;Ludtke, Steven J.
通讯作者：
Ludtke, Steven J.
影响因子：
64.8
作者：
McKern, Neil M.;Lawrence, Michael C.;Ward, Colin W.
通讯作者：
Ward, Colin W.
影响因子：
64.5
作者：
Freed DM;Bessman NJ;Kiyatkin A;Salazar-Cavazos E;Byrne PO;Moore JO;Valley CC;Ferguson KM;Leahy DJ;Lidke DS;Lemmon MA
通讯作者：
Lemmon MA