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J Mol Biol. 2006 Jan 27;355(4):821-44. Epub 2005 Nov 8.

The ubiquitin domain superfold: structure-based sequence alignments and characterization of binding epitopes.

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  • 1European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.


Ubiquitin-like domains are present, apart from ubiquitin-like proteins themselves, in many multidomain proteins involved in different signal transduction processes. The sequence conservation for all ubiquitin superfold family members is rather poor, even between subfamily members, leading to mistakes in sequence alignments using conventional sequence alignment methods. However, a correct alignment is essential, especially for in silico methods that predict binding partners on the basis of sequence and structure. In this study, using 3D-structural information we have generated and manually corrected sequence alignments for proteins of the five ubiquitin superfold subfamilies. On the basis of this alignment, we suggest domains for which structural information will be useful to allow homology modelling. In addition, we have analysed the energetic and electrostatic properties of ubiquitin-like domains in complex with various functional binding proteins using the protein design algorithm FoldX. On the basis of an in silico alanine-scanning mutagenesis, we provide a detailed binding epitope mapping of the hotspots of the ubiquitin domain fold, involved in the interaction with different domains and proteins. Finally, we provide a consensus fingerprint sequence that identifies all sequences described to belong to the ubiquitin superfold family. It is possible that the method that we describe may be applied to other domain families sharing a similar fold but having low levels of sequence homology.

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