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 using Chimera. Cartoon representation based on similar representation in. 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). 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. pTyr407 was mapped as binding site for NCK. pSer 552 allows intramolecular interaction of the loop region with the PH domain and regulates Gab1 localization. Interaction regions for PAK4 kinase, CRK-family proteins[27, 28], PI3 kinase (PIK3R1/2;) and the phosphatase SHP2 (PTPN11;) 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, while a T387N mutation abolishes a threonine residue phosphorylated after EGFR or c-Met stimulation. 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.