Structures of the modeled Tip-STAT complexes.

<p>(A) Tip and STAT structural domains (not to scale). (Top) From amino-terminus to carboxy-terminus of Tip the four tyrosine residues are displayed, the major phosphotyrosine residues Y114 and Y127 are also highlighted, along with the Lck binding domains; transmembrane region (TM). (Bottom) Schematic arrangement of STAT domains; N terminal domain (NTD), Coiled coil domain (CCD), DNA binding domain (DBD), Src homology 2 (SH2) domain, Linker domain (LD), Y tyrosine that stabilizes antiparallel conformation upon phosphorylation, and Transactivation domain (TD). (B) Multiple sequence alignment of human STAT SH2 domain sequences. Human STAT SH2 domains were aligned using CLUSTAL Omega <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034306#pone.0034306-Sievers1" target="_blank">[47]</a> and displayed with Vektor NTi (version 9). The consensus is based on residues present in more than 75% of sequences; fully conserved residues are colored in yellow, those present in more than 75% in blue, homologous amino acids are colored in green (C) Structures of the modeled Tip-STAT complexes highlighting the overall complex geometry and the main interacting regions. (top left) Tip114-STAT3, (top right) Tip127-STAT3, (bottom left) Tip114-STAT6, and (bottom right) Tip127-STAT6. The STAT SH2 domain is shown in grey space-filled presentation. The three main interacting regions are defined and colored as follows: region I (binds ligand residues pY, pY+1; orange), region II (binds pY+2, pY+3; red), region III (binds pY+4 to pY+8; cyan). The Tip ligand is shown in stick presentation and key residues belonging to different interaction regions are labeled.