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BIOPHYSICS
Detecting remotely related proteins by their interactions and sequence similarity

Jordi Espadaler ^*,  , Ramón Aragüés ^* , Narayanan Eswar , Marc A. Marti-Renom , Enrique Querol , Francesc X. Avilés , Andrej Sali ^, ¶, and Baldomero Oliva ^*, ¶

^*Laboratori de Bioinformàtica Estructural, Grup de Recerca en Informàtica Biomèdica-Institut Municipal d'Investigació Médica (GRIB-IMIM), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain; Institut de Biotecnologia i Biomedicina and Departament de Bioquímica, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain; and Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry and California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA 94143

Edited by Barry H. Honig, Columbia University, New York, NY, and approved March 31, 2005 (received for review February 1, 2005)

The function of an uncharacterized protein is usually inferred either from its homology to, or its interactions with, characterized proteins. Here, we use both sequence similarity and protein interactions to identify relationships between remotely related protein sequences. We rely on the fact that homologous sequences share similar interactions, and, therefore, the set of interacting partners of the partners of a given protein is enriched by its homologs. The approach was benchmarked by assigning the fold and functional family to test sequences of known structure. Specifically, we relied on 1,434 proteins with known folds, as defined in the Structural Classification of Proteins (SCOP) database, and with known interacting partners, as defined in the Database of Interacting Proteins (DIP). For this subset, the specificity of fold assignment was increased from 54% for position-specific iterative BLAST to 75% for our approach, with a concomitant increase in sensitivity for a few percentage points. Similarly, the specificity of family assignment at the e-value threshold of 10^-8 was increased from 70% to 87%. The proposed method would be a useful tool for large-scale automated discovery of remote relationships between protein sequences, given its unique reliance on sequence similarity and protein-protein interactions.

remote homology | fold assignment | family assignment | protein function annotation | protein-protein interactions

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: SCOP, Structural Classification of Proteins; PSI, position-specific iterative; DIP, Database of Interacting Proteins; PSSM, position-specific scoring matrix.

J.E. and R.A. contributed equally to this work.

^¶ To whom correspondence may be addressed. E-mail: sali{at}salilab.org or boliva{at}imim.es.

© 2005 by The National Academy of Sciences of the USA

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