Diversity and evolution of retinoblastoma protein-binding LxCxE motifs in human proteins

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

Oro Verde, Entre Ríos

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

Asociación Argentina de Bioinformática y Biología Computacional

Introduction The retinoblastoma tumor suppressor protein (Rb) plays a central role in eukaryotic cell cycle control, differentiation and chromatin structure regulation. Rb is the hub of a large protein interaction network. The retinoblastoma-binding LxCxE linear motif mediates a high affinity interaction between a conserved surface patch in Rb and one third (approximately 30) of human cellular Rb targets [1] and also between Rb and several oncoproteins from human viruses. In the present work we study the occurrence and evolution of LxCxE motifs present in human proteins using bioinformatics tools to identify this linear motif and to analyze its variability in homologous non-human proteins. Methods We use available linear motif databases and bibliographic search to compile a database of human Rb target proteins harboring the LxCxE motif. We annotate the structural context of the motif using the Protein Data Bank structure database [2] and the IUPRED predictor for intrinsic disorder [3]. We also characterize the sequence context of the motif using sequence logos [4] and searching for known associated motis [5]. For a subset of targets, we search for the LxCxE motif in homologous proteins from eukaryotic and prokaryotic organisms and analyze evolution of the motif. Results and conclusions We report that the LxCxE motif from human Rb protein targets can be found both within disordered and within globular domains. When present in a globular domain, the motif can occur in various secondary structure elements, suggesting that conformational transitions must take place to allow for Rb binding. We find variability in the linear motifs associated to the LxCxE motif and different conservation patterns when compared to the known instances of viral proteins. We discuss the results found for LxCxE motifs in the human proteome in the light of the information available on the Rb-LxCxE interaction and on the known features of viral LxCxE motifs. Based on these data, we suggest that host and viral LxCxE motifs may differ in their evolution and functional properties. References [1] Dick FA. Cell Div. 2007 Sep 13;2:26., [2] http://www.rcsb.org/pdb/home/home.do, [3] Dosztányi Z, Csizmók V, Tompa P and Simon I. Bioinformatics (2005) 21, 3433-3434., [4] Schneider TD, Stephens RM. 1990. Nucleic Acids Res. 18:6097-6100, [5] Chemes LB, Glavina J, Faivovich J, de Prat-Gay G, Sánchez IE. J Mol Biol. 2012. In press. DOI: 􀁉􀁕􀁕􀁑􀀛􀀐􀀐􀁅􀁙􀀏􀁅􀁐􀁊􀀏􀁐􀁓􀁈􀀐􀀒􀀑􀀏􀀒􀀑􀀒􀀗􀀐􀁋􀀏􀁋􀁎􀁃􀀏􀀓􀀑􀀒􀀓􀀏􀀑􀀖􀀏􀀑􀀔􀀗􀀏