“RKKH” Peptides from the Snake Venom Metalloproteinase ofBothrops jararaca Bind Near the Metal Ion-dependent Adhesion Site of the Human Integrin α2 I-domain

• Published in: The Journal of biological chemistry 1999-10, Vol.274 (44), p.31493
• Main Authors: Olli Pentikäinen, Anna-Marja Hoffrén, Johanna Ivaska, Jarmo KäpylÃ, Tommi Nyrönen, Jyrki Heino, Mark S. Johnson
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.44.31493

Integrin α 1 β 1 and α 2 β 1 are the major cellular receptors for collagen, and collagens bind to these integrins at the inserted I-domain in their α subunit. We have previously shown that a cyclic peptide derived from the metalloproteinase domain of the snake venom protein jararhagin blocks the collagen-binding function of the α 2 I-domain. Here, we have optimized the structure of the peptide and identified the site where the peptide binds to the α 2 I-domain. The peptide sequence Arg-Lys-Lys-His is critical for recognition by the I-domain, and five negatively charged residues surrounding the “metal ion-dependent adhesion site” (MIDAS) of the I-domain, when mutated, show significantly impaired binding of the peptide. Removal of helix αC, located along one side of the MIDAS and suggested to be involved in collagen-binding in these I-domains, does not affect peptide binding. This study supports the notion that the metalloproteinase initially binds to the α 2 I-domain at a location distant from the active site of the protease, thus blocking collagen binding to the adhesion molecule in the vicinity of the MIDAS, while at the same time leaving the active site free to degrade nearby proteins, the closest being the β 1 subunit of the α 2 β 1 cell-surface integrin itself.