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 language | English (US) |
|---|---|
| Pages (from-to) | 9657-9665 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 282 |
| Issue number | 13 |
| DOIs | |
| State | Published - Mar 30 2007 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
Cite this
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 journal › Article
}
TY - JOUR
T1 - Structure-function analysis of Arg-Gly-Asp helix motifs in αvβ6 integrin ligands
AU - DiCara, Danielle
AU - Rapisarda, Chiara
AU - Sutcliffe, Julie
AU - Violette, Shelia M.
AU - Weinreb, Paul H.
AU - Hart, Ian R.
AU - Howard, Mark J.
AU - Marshall, John F.
PY - 2007/3/30
Y1 - 2007/3/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34248193368&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34248193368&partnerID=8YFLogxK
U2 - 10.1074/jbc.M610461200
DO - 10.1074/jbc.M610461200
M3 - Article
C2 - 17244604
AN - SCOPUS:34248193368
VL - 282
SP - 9657
EP - 9665
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 13
ER -