Haxholm Gitte W, Nikolajsen Louise F, Olsen Johan G, Fredsted Jacob, Larsen Flemming H, Goffin Vincent, Pedersen Stine F, Brooks Andrew J, Waters Michael J, Kragelund Birthe B
Structural Biology and NMR Laboratory (SBiNLab), Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
Cell and Developmental Biology, Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark.
Biochem J. 2015 Jun 15;468(3):495-506. doi: 10.1042/BJ20141243. Epub 2015 Apr 7.
Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors and may implicate the membrane as an active component regulating intracellular signalling.
1类细胞因子受体通过复杂的细胞内信号网络调节重要的生物学过程。然而，由于严重缺乏对细胞内结构域（ICD）的结构-功能研究，目前理解其功能的结构平台尚不完整。本研究首次对任何细胞因子受体ICD进行了全面的结构表征，并证明人催乳素（PRL）受体（PRLR）和生长激素受体（GHR）的ICD在其全长范围内本质上是无序的。我们表明，它们通过类似于基于免疫受体酪氨酸的激活基序（ITAM）的保守基序与质膜内小叶的标志性脂质特异性相互作用。然而，与对ITAM的观察结果相反，PRLR和GHR ICD与脂质的结合并未伴随着瞬时二级结构的变化，且与酪氨酸磷酸化无关。本研究结果为研究1类细胞因子受体提供了一个新的结构平台，并可能暗示膜是调节细胞内信号传导的活性成分。
