Structure-function analysis of Arg-Gly-Asp helix motifs in αvβ6 integrin ligands

Danielle DiCara, Chiara Rapisarda, Julie Sutcliffe, Shelia M. Violette, Paul H. Weinreb, Ian R. Hart, Mark J. Howard, John F. Marshall

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)9657-9665
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number13
DOIs
StatePublished - Mar 30 2007

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Integrins
Viperidae
Ligands
Peptides
Virus Latency
Foot-and-Mouth Disease Virus
Hydrophobic and Hydrophilic Interactions
Viruses
Testing

ASJC Scopus subject areas

  • Biochemistry

Cite this

DiCara, D., Rapisarda, C., Sutcliffe, J., Violette, S. M., Weinreb, P. H., Hart, I. R., ... Marshall, J. F. (2007). Structure-function analysis of Arg-Gly-Asp helix motifs in αvβ6 integrin ligands. Journal of Biological Chemistry, 282(13), 9657-9665. https://doi.org/10.1074/jbc.M610461200

Structure-function analysis of Arg-Gly-Asp helix motifs in αvβ6 integrin ligands. / DiCara, Danielle; Rapisarda, Chiara; Sutcliffe, Julie; Violette, Shelia M.; Weinreb, Paul H.; Hart, Ian R.; Howard, Mark J.; Marshall, John F.

In: Journal of Biological Chemistry, Vol. 282, No. 13, 30.03.2007, p. 9657-9665.

Research output: Contribution to journalArticle

DiCara, D, Rapisarda, C, Sutcliffe, J, Violette, SM, Weinreb, PH, Hart, IR, Howard, MJ & Marshall, JF 2007, 'Structure-function analysis of Arg-Gly-Asp helix motifs in αvβ6 integrin ligands', Journal of Biological Chemistry, vol. 282, no. 13, pp. 9657-9665. https://doi.org/10.1074/jbc.M610461200
DiCara, Danielle ; Rapisarda, Chiara ; Sutcliffe, Julie ; Violette, Shelia M. ; Weinreb, Paul H. ; Hart, Ian R. ; Howard, Mark J. ; Marshall, John F. / Structure-function analysis of Arg-Gly-Asp helix motifs in αvβ6 integrin ligands. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 13. pp. 9657-9665.
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