title: The putative role of some conserved water molecules in the structure and function of human transthyretin.
abstract: Human transthyretin (hTTR) is a multifunctional protein that is involved in several neurodegenerative diseases. Besides the transportation of thyroxin and vitamin A, it is also involved in the proteolysis of apolipoprotein A1 and Aβ peptide. Extensive analyses of 32 high-resolution X-ray and neutron diffraction structures of hTTR followed by molecular-dynamics simulation studies using a set of 15 selected structures affirmed the presence of 44 conserved water molecules in its dimeric structure. They are found to play several important roles in the structure and function of the protein. Eight water molecules stabilize the dimeric structure through an extensive hydrogen-bonding network. The absence of some of these water molecules in highly acidic conditions (pH ≤ 4.0) severely affects the interfacial hydrogen-bond network, which may destabilize the native tetrameric structure, leading to its dissociation. Three pairs of conserved water molecules contribute to maintaining the geometry of the ligand-binding cavities. Some other water molecules control the orientation and dynamics of different structural elements of hTTR. This systematic study of the location, absence, networking and interactions of the conserved water molecules may shed some light on various structural and functional aspects of the protein. The present study may also provide some rational clues about the conserved water-mediated architecture and stability of hTTR.
authors.affiliation: Department of Chemistry, National Institute of Technology-Durgapur, Durgapur 713 209, India.
authors.forename: Avik
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, National Institute of Technology-Durgapur, Durgapur 713 209, India.
authors.forename: Subrata
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Chemistry, National Institute of Technology-Durgapur, Durgapur 713 209, India.
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Mukhopadhyay
authors.affiliation: Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Kanagaraj
authors.initials: K
authors.lastname: Sekar
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D056004:Molecular Dynamics Simulation; D011228:Prealbumin / Q000737:chemistry*; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D014867:Water / Q000737:chemistry*
chemical_list: D011228:Prealbumin; D014867:Water
keywords: X-ray structure analysis; conserved water; human transthyretin; hydrogen bonding; molecular-dynamics simulation