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Published online before print December 1, 2005, 10.1110/ps.051787106
Protein Science (2006), 15:28-32. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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ACCELERATED COMMUNICATION

A structural model of an amyloid protofilament of Transthyretin

Bruno E. Correia1,3, Nuno Loureiro-Ferreira2,3, J. Rui Rodrigues2 and Rui M.M. Brito1,2

1 Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal
2 Centro de Neurociências de Coimbra, Universidade de Coimbra, 3004-517 Coimbra, Portugal

(RECEIVED August 17, 2005; FINAL REVISION October 6, 2005; ACCEPTED October 12, 2005)

A docking-and-alignment protocol was devised in order to build amyloid protofilaments of Transthyretin (TTR), starting from partially disrupted TTR monomeric subunits and based on experimentally available information. The docking approach is driven by a combination of shape complementarity and energetic criteria, and uses constraints derived from experimental data obtained for the fibrillar state. The dimeric structures obtained were then subjected to an alignment scheme followed by clustering analysis, producing a collection of protofilaments with distinct geometric properties. The selected protofilament model presented here does agree with known experimental data and general amyloid properties; it is formed by two extended continuous {beta}-sheets with the {beta}-strands perpendicular to the main axis of the protofilament and a helical twist with a period of ~48 {beta}-strands. This TTR proto-filament model may be an important step in the understanding of the molecular mechanisms of TTR aggregation, as well as, a valuable instrument in drug design strategies against amyloid diseases.

Keywords: Transthyretin; amyloid; protofilament; protein docking; supramolecular assembly

Abbreviations: EPR, electron paramagnetic resonance • NearNI, near-native interface • NonNI, non-native interface • TTR, Transthyretin

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051787106.

Reprint requests to: Rui M.M. Brito, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal; e-mail: brito{at}ci.uc.pt; fax: +351-239-827703.


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