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Localization of protein-binding sites within families of proteins

¹ Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, and California Institute for Quantitative Biomedical Research, and ² Graduate Group in Biophysics, University of California at San Francisco, San Francisco, California 94143, USA

(RECEIVED May 5, 2005; FINAL REVISION May 27, 2005; ACCEPTED May 27, 2005)

We address the question of whether or not the positions of protein-binding sites on homologous protein structures are conserved irrespective of the identities of their binding partners. First, for each domain family in the Structural Classification of Proteins (SCOP), protein-binding sites are extracted from our comprehensive database of structurally defined binary domain interactions (PIBASE). Second, the binding sites within each family are superposed using a structural alignment of its members. Finally, the degree of localization of binding sites within each family is quantified by comparing it with localization expected by chance. We found that 72% of the 1847 SCOP domain families in PIBASE have binding sites with localization values greater than expected by chance. Moreover, 554 (30%) of these families have localizations that are statistically significant (i.e., more than four standard deviations away from the mean expected by chance). In contrast, only 144 (8%) families have significantly low localization. The absence of a significant correlation of the binding site localization with the average sequence and structural conservations in a family suggests that localization can be helpful for describing the functional diversity of protein–protein interactions, complementing measures of sequence and structural conservation. Consideration of the binding site localization may also result in spatial restraints for the modeling of protein assembly structures.

Keywords: protein–protein interactions; protein interfaces; binding sites; evolution; protein family

Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051571905.

Reprint requests to: Andrej Sali, 1700 4th Street, Suite 503B, University of California at San Francisco, San Francisco, CA 94143-2552, USA; e-mail: sali{at}salilab.org; fax: (415) 514-4231. Article published online ahead of print.

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