Structural basis of TRPV5 regulation by physiological and pathophysiological modulators.
Structural basis of TRPV5 regulation by physiological and pathophysiological modulators.
复制标题
DOI：
10.1016/j.celrep.2022.110737
复制
发表时间：
2022-04-26
期刊：
影响因子：
8.8
通讯作者：
Moiseenkova-Bell, Vera Y.
中科院分区：
文献类型：
--
作者：
Fluck, Edwin C.;Yazici, Aysenur Torun;Rohacs, Tibor;Moiseenkova-Bell, Vera Y.
瞬时受体电位香草酸5（TRPV 5）是一种肾脏特异性钙离子通道，在钙稳态中起关键作用。TRPV 5的基础活性通过磷脂酰肌醇4，5-二磷酸（PI（4，5）P2）的激活和Ca 2+结合的钙调蛋白（CaM）的抑制来平衡。甲状旁腺激素（PTH）是钙稳态的关键外源性调节因子，通过蛋白激酶A（PKA）介导的磷酸化增加TRPV 5的活性。代谢性酸中毒导致TRPV 5活性降低，不依赖于PTH，引起高钙尿症。使用冷冻电子显微镜（cryo-EM），我们表明，低pH抑制TRPV 5通过排除PI（4，5）P2激活。我们在低pH值下捕获中间构象，揭示了从开放到封闭状态的转变。此外，我们证明PI（4，5）P2是通道门控的主要调节剂，而PKA通过阻止CaM结合和通道失活来控制TRPV 5活性。我们的数据提供了两个关键的外源性调节剂，低pH和PKA的TRPV 5的调节的详细分子机制。Fluck等人研究了TRPV 5的活性如何被酸性pH环境降低以及如何被PKA磷酸化增加。结合cryo-EM和电生理学，他们的结果表明，酸性环境导致通道关闭和PI（4，5）P2结合的损失，而PKA磷酸化破坏CaM失活。
Transient receptor potential vanilloid 5 (TRPV5) is a kidney-specific Ca2+-selective ion channel that plays a key role in Ca2+ homeostasis. The basal activity of TRPV5 is balanced through activation by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and inhibition by Ca2+-bound calmodulin (CaM). Parathyroid hormone (PTH), the key extrinsic regulator of Ca2+ homeostasis, increases the activity of TRPV5 via protein kinase A (PKA)-mediated phosphorylation. Metabolic acidosis leads to reduced TRPV5 activity independent of PTH, causing hypercalciuria. Using cryoelectron microscopy (cryo-EM), we show that low pH inhibits TRPV5 by precluding PI(4,5)P2 activation. We capture intermediate conformations at low pH, revealing a transition from open to closed state. In addition, we demonstrate that PI(4,5)P2 is the primary modulator of channel gating, yet PKA controls TRPV5 activity by preventing CaM binding and channel inactivation. Our data provide detailed molecular mechanisms for regulation of TRPV5 by two key extrinsic modulators, low pH and PKA. Fluck et al. investigate how the activity of TRPV5 is decreased by acidic pH environments and increased by PKA phosphorylation. Combining cryo-EM and electrophysiology, their results show that acidic environments cause channel closing and loss of PI(4,5)P2 binding, whereas PKA phosphorylation disrupts CaM inactivation.
登录
查看更多内容
影响因子：
48
作者：
Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
通讯作者：
Fraser JS
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：
13.6
作者：
de Groot, Theun;Lee, Kyupil;Hoenderop, Joost G. J.
通讯作者：
Hoenderop, Joost G. J.
DOI：
10.1073/pnas.1820323116
发表时间：
2019-04-30
影响因子：
11.1
作者：
Dang, Shangyu;van Goor, Mark K.;van der Wijst, Jenny
通讯作者：
van der Wijst, Jenny
盐桥：几何特异性，可设计的相互作用。
影响因子：
2.9
作者：
Donald, Jason E.;Kulp, Daniel W.;DeGrado, William F.
通讯作者：
DeGrado, William F.