Investigating Phosphorylation-Induced Conformational Changes in WNK1 Kinase by Molecular Dynamics Simulations.

Nisha Amarnath Jonniya,Parimal Kar,Md Fulbabu Sk

doi:10.1021/acsomega.9b02187

Nisha Amarnath Jonniya, Parimal Kar + Show 1 more

Open Access

https://doi.org/10.1021/acsomega.9b02187

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Journal: ACS omega	Publication Date: Oct 11, 2019
Citations: 46	License type: cc-by

Affiliation: Indian Institute of Technology Indore

Abstract

The With-No-Lysine (WNK) kinase is considered to be a master regulator for various cation-chloride cotransporters involved in maintaining cell-volume and ion homeostasis. Here, we have investigated the phosphorylation-induced structural dynamics of the WNK1 kinase bound to an inhibitor via atomistic molecular dynamics simulations. Results from our simulations show that the phosphorylation at Ser382 could stabilize the otherwise flexible activation loop (A-loop). The intrahelix salt-bridge formed between Arg264 and Glu268 in the unphosphorylated system is disengaged after the phosphorylation, and Glu268 reorients itself and forms a stable salt-bridge with Arg348. The dynamic cross-correlation analysis shows that phosphorylation diminishes anticorrelated motions and increases correlated motions between different domains. Structural network analysis reveals that the phosphorylation causes structural rearrangements and shortens the communication path between the αC-helix and catalytic loop, making the binding pocket more suitable for accommodating the ligand. Overall, we have characterized the structural changes in the WNK kinase because of phosphorylation in the A-loop, which might help in designing rational drugs.

Highlights

Hypertension or high blood pressure is a common disorder affecting billion people worldwide.[1]
The WNK signaling pathway that is involved in regulating blood pressure participates in the activation of its downstream kinases, such as oxidative stressresponsive kinase 1 (OSR1) and STE20/SPS1-related proline/ alanine-rich kinase (SPAK) being phosphorylated by WNK1 and WNK4, which in turn phosphorylate and activate the Na+/ Cl− cotransporter (NCC).[4,5]
It is evident from the figure that in the case of uWNK, the system drifts from its initial structure till 100 ns and again there is a sudden jump in rmsd at 360 ns, and slowly it reaches a plateau after 480 ns

Summary

Introduction

Hypertension or high blood pressure is a common disorder affecting billion people worldwide.[1] It leads to various other disease conditions, such as myocardial infarction, renal failure, and congestive heart failure. Available antihypertensive drugs help to control blood pressure, the emergence of the drug-resistant variant has created a global challenge in treating hypertension. Gene mutations involved in the pathway of renal salt reabsorption could affect the blood pressure. The WNK signaling pathway that is involved in regulating blood pressure participates in the activation of its downstream kinases, such as oxidative stressresponsive kinase 1 (OSR1) and STE20/SPS1-related proline/ alanine-rich kinase (SPAK) being phosphorylated by WNK1 and WNK4, which in turn phosphorylate and activate the Na+/ Cl− cotransporter (NCC).[4,5] The inhibiting function of WNK is considered as an effective approach for controlling blood pressure

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