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|Title:||Structural analysis on mutation residues and interfacial water molecules for human TIM disease understanding||Authors:||Li, Zhenhua
Kwoh, Chee Keong
|Keywords:||DRNTU::Engineering::Computer science and engineering::Computer applications::Life and medical sciences||Issue Date:||2013||Source:||Li, Z., He, Y., Liu, Q., Zhao, L., Wong, L., Kwoh, C. K., et al. (2013). Structural analysis on mutation residues and interfacial water molecules for human TIM disease understanding. BMC bioinformatics, 14(Suppl 16), S11.||Series/Report no.:||BMC bioinformatics||Abstract:||Background: Human triosephosphate isomerase (HsTIM) deficiency is a genetic disease caused often by the pathogenic mutation E104D. This mutation, located at the side of an abnormally large cluster of water in the inter-subunit interface, reduces the thermostability of the enzyme. Why and how these water molecules are directly related to the excessive thermolability of the mutant have not been investigated in structural biology. Results: This work compares the structure of the E104D mutant with its wild type counterparts. It is found that the water topology in the dimer interface of HsTIM is atypical, having a "wet-core-dry-rim" distribution with 16 water molecules tightly packed in a small deep region surrounded by 22 residues including GLU104. These water molecules are co-conserved with their surrounding residues in non-archaeal TIMs (dimers) but not conserved across archaeal TIMs (tetramers), indicating their importance in preserving the overall quaternary structure. As the structural permutation induced by the mutation is not significant, we hypothesize that the excessive thermolability of the E104D mutant is attributed to the easy propagation of atoms' flexibility from the surface into the core via the large cluster of water. It is indeed found that the B factor increment in the wet region is higher than other regions, and, more importantly, the B factor increment in the wet region is maintained in the deeply buried core. Molecular dynamics simulations revealed that for the mutant structure at normal temperature, a clear increase of the root-mean-square deviation is observed for the wet region contacting with the large cluster of interfacial water. Such increase is not observed for other interfacial regions or the whole protein. This clearly suggests that, in the E104D mutant, the large water cluster is responsible for the subunit interface flexibility and overall thermolability, and it ultimately leads to the deficiency of this enzyme. Conclusions: Our study reveals that a large cluster of water buried in protein interfaces is fragile and high-maintenance, closely related to the structure, function and evolution of the whole protein.||URI:||https://hdl.handle.net/10356/101425
|ISSN:||1471-2105||DOI:||10.1186/1471-2105-14-S16-S11||Rights:||© 2013 The Authors, licensee BioMed Central Ltd. This paper was published in BMC Bioinformatics and is made available as an electronic reprint (preprint) with permission of the authors. The paper can be found at the following official DOI: [http://dx.doi.org/10.1186/1471-2105-14-S16-S11]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
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