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The putative role of some conserved water molecules in the structure and function of human transthyretin

Banerjee, Avik and Dasgupta, Subrata and Mukhopadhyay, Bishnu P and Sekar, Kanagaraj (2015) The putative role of some conserved water molecules in the structure and function of human transthyretin. In: ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 71 (11). pp. 2248-2266.

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Official URL: http://dx.doi.org/10.1107/S1399004715016004

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 A beta 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.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the INT UNION CRYSTALLOGRAPHY, 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND
Keywords: human transthyretin; X-ray structure analysis; conserved water; hydrogen bonding; molecular-dynamics simulation
Department/Centre: Division of Interdisciplinary Research > Supercomputer Education & Research Centre
Depositing User: Id for Latest eprints
Date Deposited: 10 Dec 2015 06:02
Last Modified: 10 Dec 2015 06:02
URI: http://eprints.iisc.ac.in/id/eprint/52876

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