Structure-Function Analysis of Arg-Gly-Asp Helix Motifs in αvβ6 Integrin Ligands

• Published in: The Journal of biological chemistry 2007-03, Vol.282 (13), p.9657
• Main Authors: Danielle DiCara, Chiara Rapisarda, Julie L. Sutcliffe, Shelia M. Violette, Paul H. Weinreb, Ian R. Hart, Mark J. Howard, John F. Marshall
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M610461200

Data relating to the structural basis of ligand recognition by integrins are limited. Here we describe the physical requirements for high affinity binding of ligands to αvβ6. By combining a series of structural analyses with functional testing, we show that 20-mer peptide ligands, derived from high affinity ligands of αvβ6 (foot-and-mouth-disease virus, latency associated peptide), have a common structure comprising an Arg-Gly-Asp motif at the tip of a hairpin turn followed immediately by a C-terminal helix. This arrangement allows two conserved Leu/Ile residues at Asp +1 and Asp +4 to be presented on the outside face of the helix enabling a potential hydrophobic interaction with the αvβ6 integrin, in addition to the Arg-Gly-Asp interaction. The extent of the helix determines peptide affinity for αvβ6 and potency as an αvβ6 antagonist. A major role of this C-terminal helix is likely to be the correct positioning of the Asp +1 and Asp +4 residues. These data suggest an explanation for several biological functions of αvβ6 and provide a structural platform for design of αvβ6 antagonists.