Figure 1

Selected examples for different functional types of loops in large biomolecules. A. Atrial natriuretic peptide hormones contain vital ‘activity conferring’ loops (green) generated in each case by a single disulfide bond (red). Shown here is the solution conformation and cartoon representation of one ANP variant. Solution conformation generated from PDB database entry 1ANP[16] using Chimera[17]. Cartoon representation based on similar representation in[18]. B. The ‘intramolecular docking’ loop (green) in the c-Crk II protein regulates the overall conformation of its SH2 (red), SH3N (dark blue) and SH3C (light blue) domains by an inducible intramolecular interaction between the SH2 domain and a phosphorylated tyrosine residue (yellow) in the loop region. Structural representation generated from PDB entry 2DVJ (aa 1-228; SH2, SH3N and loop) and PDB entry 2EYZ (aa 229-304; loop and SH3C)[15]. C. Gab1 contains an N-terminal PH domain (grey shaded area) followed by a largely unstructured region (green) with numerous sites for potential intra- and intermolecular interactions (yellow: tyrosine-phosphorylation sites, red: serine-phosphorylation site, orange and purple: secondary structure elements). This ‘signal computation’ loop permits the assembly of and signaling via context-specific complexes[19, 20]. The poly-proline type II helix (PP II) and the 3₁₀ helix (3₁₀) in Gab1 and its close relative Gab2 can interact with the Grb2 adapter protein[21, 22]. Cortactin was also reported to interact with these regions[23]. pTyr407 was mapped as binding site for NCK[24]. pSer 552 allows intramolecular interaction of the loop region with the PH domain and regulates Gab1 localization[25]. Interaction regions for PAK4 kinase[26], CRK-family proteins[27, 28], PI3 kinase (PIK3R1/2;[29]) and the phosphatase SHP2 (PTPN11;[30]) have been described. WASL (N-WASP) may interact directly with the PH domain (Richard Vaillancourt, Morag Park et al.; personal communication). Elements associated with specific cellular functions like cell motility, survival or proliferation are often found co-localized in defined regions of the signaling loop. Y83 and T387 are two residues mutated in breast cancer. The Y83C mutation could interfere with PI(3,4,5)P3 binding of the PH domain[25], while a T387N mutation abolishes a threonine residue phosphorylated after EGFR or c-Met stimulation[31]. Structural representation of PH domain generated from PDB entry 2X18. D. A ‘signal computation’ loop (green) in a DNA molecule controls transcriptional activity by bringing locus control region (LCR) and promoter region together in the presence of a crucial transcription factor (red: GATA1). Based on a similar figure in[1].