Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis.
Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis.
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DOI：
10.1073/pnas.2220851120
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发表时间：
2023-06-06
影响因子：
11.1
通讯作者：
Kvansakul, Marc
中科院分区：
文献类型：
--
作者：
Stewart, Bryce Z.;Mamonova, Tatyana;Sneddon, W. Bruce;Javorsky, Airah;Yang, Yanmei;Wang, Bin;Nolin, Thomas D.;Humbert, Patrick O.;Friedman, Peter A.;Kvansakul, Marc
G蛋白偶联受体如PTHR严格控制代谢过程，包括血清磷酸盐和维生素D水平。我们现在表明，与细胞极性调节衔接蛋白Scribble的直接相互作用控制PTHR活性。Scribble使用其PDZ 1和PDZ 3结构域在PTHR C-末端接合短序列基序，以微摩尔亲和力结合。这种相互作用的丧失影响Scribble KO小鼠的血清磷酸盐和维生素D水平。我们的发现揭示了肾脏代谢和细胞极性信号之间的意外联系。G蛋白偶联受体，包括PTHR，对于控制从血清磷酸盐和维生素D水平到葡萄糖摄取的代谢过程是关键的，并且细胞质相互作用物可以调节它们的信号传导、运输和功能。我们现在表明，直接相互作用与Scribble，细胞极性调节衔接蛋白，调节PTHR活性。Scribble是建立和发展组织结构的关键调节剂，其失调涉及各种疾病，包括肿瘤扩张和病毒感染。Scribble与PTHR共定位于极化细胞的基底和侧表面。使用X射线晶体学，我们表明共定位是通过使用Scribble PDZ 1和PDZ 3结构域在PTHR C末端接合短序列基序介导的，结合亲和力分别为31.7和13.4 μM。由于PTHR通过对肾近端小管的作用控制代谢功能，我们设计小鼠以选择性敲除近端小管中的Scribble。Scribble的丢失影响血清磷酸盐和维生素D水平，并导致血浆磷酸盐显著升高和聚集维生素D3水平增加，而血糖水平保持不变。总的来说，这些结果确定Scribble作为PTHR介导的信号和功能的重要调节剂。我们的发现揭示了肾脏代谢和细胞极性信号之间的意外联系。
G protein-coupled receptors such as PTHR critically control metabolic processes, including serum phosphate and vitamin D levels. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, controls PTHR activity. Scribble engages a short sequence motif at the PTHR C-terminus using its PDZ1 and PDZ3 domain to bind with micromolar affinities. The loss of this interaction impacts serum phosphate and vitamin D levels in Scribble KO mice. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling. G protein-coupled receptors, including PTHR, are pivotal for controlling metabolic processes ranging from serum phosphate and vitamin D levels to glucose uptake, and cytoplasmic interactors may modulate their signaling, trafficking, and function. We now show that direct interaction with Scribble, a cell polarity-regulating adaptor protein, modulates PTHR activity. Scribble is a crucial regulator for establishing and developing tissue architecture, and its dysregulation is involved in various disease conditions, including tumor expansion and viral infections. Scribble co-localizes with PTHR at basal and lateral surfaces in polarized cells. Using X-ray crystallography, we show that colocalization is mediated by engaging a short sequence motif at the PTHR C-terminus using Scribble PDZ1 and PDZ3 domain, with binding affinities of 31.7 and 13.4 μM, respectively. Since PTHR controls metabolic functions by actions on renal proximal tubules, we engineered mice to selectively knockout Scribble in proximal tubules. The loss of Scribble impacted serum phosphate and vitamin D levels and caused significant plasma phosphate elevation and increased aggregate vitamin D3 levels, whereas blood glucose levels remained unchanged. Collectively these results identify Scribble as a vital regulator of PTHR-mediated signaling and function. Our findings reveal an unexpected link between renal metabolism and cell polarity signaling.
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影响因子：
4.7
作者：
Hirano S;Goto R;Uchida Y
通讯作者：
Uchida Y
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
KAUFMANN, M;MUFF, R;FISCHER, JA
通讯作者：
FISCHER, JA
影响因子：
5.8
作者：
Khundmiri, Syed Jalal;Murray, Rebecca D.;Lederer, Eleanor
通讯作者：
Lederer, Eleanor
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH