Identification of putative LxCxE motifs targeting the retinoblastoma protein in human viruses by structure- and sequence-based calculations

GLAVINA, J; CHEMES, L.B.; DE PRAT-GAY, G.; SANCHEZ, IE

Oro Verde, Entre Ríos

Conferencia; 3er Congreso Argentino de Bioinformática y Biología Computacional; 2012

Asociación Argentina de Bioinformática y Biología Computacional

Introduction Many protein functions can be described in terms of “linear sequence motifs” of less than five function-determining residues. The LxCxE motif interacts with the retinoblastoma tumor suppressor (Rb), which plays a key role in cell cycle progression. The LxCxE motif was identified in several proteins from RNA and DNA viruses, suggesting the LxCxE motif may be present in other viral proteins. We have developed a method to predict the affinity of a sequence stretch to the retinoblastoma protein using a combination of structure- and sequence-based calculations. Methods Structure-based calculations used FoldX, which is an empirical force field for the prediction of the stability of proteins and protein complexes [1]. We used the LxCxE-Rb complex structure to compute a first position specific scoring matrix. Sequence-based calculations used molecular information theory, which makes use of residue statistics at an alignment of known binding motifs [2]. We used over 200 sequences of LxCxE motifs from the papillomavirus E7 protein to compute a second position specific scoring matrix. Finally, we used the new algorithm to scan all known sequences from human viruses. Conclusions The combination of structure-based calculations and sequence-based calculations is able to reproduce quantitative and semi-quantitative binding experiments from the literature, the identification of known instances of the LxCxE motif and of novel putative LxCxE motifs. We discuss the list in the light of the structural and functional properties of the protein containing each motif. Acknowledgements We acknowledge funding from Agencia Nacional de Promoción Científica y Tecnológica (PICT 2010- 1052 to I.E.S), Consejo Nacional de Investigaciones Científicas y Técnicas (postdoctoral fellowship to L.B.C; G.d.P.G., and I.E.S. are CONICET career investigators) and Instituto Nacional del Cáncer (graduate fellowship to J.G.). References 1. Guerois R, Nielsen JE, Serrano L. Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 2002 , 320: 369-387. 2. Schneider TD, Stormo GD, Gold L, Ehrenfeucht A. Information content of binding sites on nucleotide sequences. J Mol Biol 1986. 188: 415-431.