Jararhagin-derived RKKH Peptides Induce Structural Changes in α1I Domain of Human Integrin α1β1

• Published in: The Journal of biological chemistry 2004-02, Vol.279 (9), p.7962
• Main Authors: Yvonne Nymalm, J. Santeri Puranen, Thomas K. M. Nyholm, Jarmo KäpylÃ, Heidi Kidron, Olli T. Pentikäinen, Tomi T. Airenne, Jyrki Heino, J. Peter Slotte, Mark S. Johnson, Tiina A. Salminen
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M312912200

Integrin α 1 β 1 is one of four collagen-binding integrins in humans. Collagens bind to the αI domain and in the case of α 2 I collagen binding is competitively inhibited by peptides containing the RKKH sequence and derived from the metalloproteinase jararhagin of snake venom from Bothrops jararaca. In α 2 I, these peptides bind near the metal ion-dependent adhesion site (MIDAS), where a collagen (I)-like peptide is known to bind; magnesium is required for binding. Published structures of the ligand-bound “open” conformation of α 2 I differs significantly from the “closed” conformation seen in the structure of apo-α 2 I near MIDAS. Here we show that two peptides, CTRKKHDC and CARKKHDC, derived from jararhagin also bind to α 1 I and competitively inhibit collagen I binding. Furthermore, calorimetric and fluorimetric measurements show that the structure of the complex of α 1 I with Mg 2+ and CTRKKHDC differs from structure in the absence of peptide. A comparison of the x-ray structure of apo-α 1 I (“closed” conformation) and a model structure of the α 1 I (“open” conformation) based on the closely related structure of α 2 I reveals that the binding site is partially blocked to ligands by Glu 255 and Tyr 285 in the “closed” structure, whereas in the “open” structure helix C is unwound and these residues are shifted, and the “RKKH” peptides fit well when docked. The “open” conformation of α 2 I resulting from binding a collagen (I)-like peptide leads to exposure of hydrophobic surface, also seen in the model of α 1 I and shown experimentally for α 1 I using a fluorescent hydrophobic probe.