Molecular Dynamic Simulation to Explore the Molecular Basis of Btk‐PH Domain Interaction with Ins(1,3,4,5)P4

Dan Lu,Zhongjie Liang,Cheng Luo,Guang Hu,Junfeng Jiang,Maomin Sun,Bairong Shen

doi:10.1155/2013/580456

Dan Lu, Zhongjie Liang + Show 5 more

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https://doi.org/10.1155/2013/580456

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Abstract

Bruton's tyrosine kinase contains a pleckstrin homology domain, and it specifically binds inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4), which is involved in the maturation of B cells. In this paper, we studied 12 systems including the wild type and 11 mutants, K12R, S14F, K19E, R28C/H, E41K, L11P, F25S, Y40N, and K12R-R28C/H, to investigate any change in the ligand binding site of each mutant. Molecular dynamics simulations combined with the method of molecular mechanics/Poisson-Boltzmann solvent-accessible surface area have been applied to the twelve systems, and reasonable mutant structures and their binding free energies have been obtained as criteria in the final classification. As a result, five structures, K12R, K19E, R28C/H, and E41K mutants, were classified as “functional mutations,” whereas L11P, S14F, F25S, and Y40N were grouped into “folding mutations.” This rigorous study of the binding affinity of each of the mutants and their classification provides some new insights into the biological function of the Btk-PH domain and related mutation-causing diseases.

Highlights

Bruton’s tyrosine kinase (Btk) is a member of the Tec family of kinases and the only known one associated with human disease [1, 2]
We have studied Btk-pleckstrin homology (PH) domain binding with the Ins(1,3,4,5)P4 structure in wild type and 11 wellknown mutants [24, 25, 27], L11P, K12R, S14F, K19E, F25S, R28C/H, Y40N, E41K, and K12R-R28C/H
It was believed that R28C, R28H, L11P, S14F, F25S, and Y40N mutants might share some similar instabilities, which was in good accordance with the predefined classifications based on experimental results [27]

Summary

Introduction

Bruton’s tyrosine kinase (Btk) is a member of the Tec family of kinases and the only known one associated with human disease [1, 2]. Studies have shown that XLA mutations in Btk can be mapped to all five domains of the kinase, which are critical for signal transmission. The PH domain is responsible for binding with phosphatidylinositols, showing the importance for the regulation of membrane targeting. A mutation in the PH domain can influence the binding affinity with a ligand, membrane targeting, and the activation of Btk [13, 14]. The Btk-PH domain has higher specificity and binding affinity with inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) [15,16,17]. The crystal structure of a complex of the Btk-PH domain with Ins(1,3,4,5)P4 (PDB ID code: 2Z0P [18]) shows that the Btk-PH domain recognizes Ins(1,3,4,5)P4 in a canonical manner [19, 20]

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