Molecular Mechanism of Na+,K+-ATPase Malfunction in Mutations Characteristic of Adrenal Hypertension
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- 作者：Wojciech Kopec ; Bastien Loubet ; Hanne Poulsen ; Himanshu Khandelia
- 刊名：Biochemistry
- 出版年：2014
- 出版时间：February 4, 2014
- 年：2014
- 卷：53
- 期：4
- 页码：746-754
- 全文大小：542K
- ISSN：1520-4995
文摘
Mutations within ion-transporting proteins may severely affect their ability to traffic ions properly and thus perturb the delicate balance of ion gradients. Somatic gain-of-function mutations of the Na+,K+-ATPase 伪1-subunit have been found in aldosterone-producing adenomas that are among the causes of hypertension. We used molecular dynamics simulations to investigate the structural consequences of these mutations, namely, Leu97 substitution by Arg (L97R), Val325 substitution by Gly (V325G), deletion of residues 93鈥?7 (Del93鈥?7), and deletion鈥搒ubstitution of residues 953鈥?56 by Ser (EETA956S), which shows inward leak currents under physiological conditions. The first three mutations affect the structural context of the key ion-binding residue Glu327 at binding site II, which leads to the loss of the ability to bind ions correctly and to occlude the pump. The mutated residue in L97R is more hydrated, which ultimately leads to the observed proton leak. V325G mimics the structural behavior of L97R; however, it does not promote the hydration of surrounding residues. In Del93鈥?7, a broader opening is observed because of the rearrangement of the kinked transmembrane helix 1, M1, which may explain the sodium leak measured with the mutant. The last mutant, EETA956S, opens an additional water pathway near the C-terminus, affecting the III sodium-specific binding site. The results are in excellent agreement with recent electrophysiology measurements and suggest how three mutations prevent the occlusion of the Na+,K+-ATPase, with the possibility of transforming the pump into a passive ion channel, whereas the fourth mutation provides insight into the sodium binding in the E1 state.