Interdomain tilt angle determines integrin-dependent function of the ninth and tenth fIII domains of human fibronectin

H. Altroff, R. Schlinkert, C.F. Van Der Walle, A. Bernini, I.D. Campbell, J.M. Werner, H.J. Mardon

Research output: Contribution to journalArticle

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Abstract

Integrins are an important family of signaling receptors that mediate diverse cellular processes. The binding of the abundant extracellular matrix ligand fibronectin to integrins α5β1 and αvβ3 is known to depend upon the Arg-Gly-Asp (RGD) motif on the tenth fibronectin FIII domain. The adjacent ninth FIII domain provides a synergistic effect on RGD-mediated integrin α5β1 binding and downstream function. The precise molecular basis of this synergy remains elusive. Here we have dissected further the function of FIII9 in integrin binding by analyzing the biological activity of the FIII9-10 interdomain interface variants and by determining their structural and dynamic properties in solution. We demonstrate that the contribution of FIII9 to both α5β1 and αvβ3 binding and downstream function critically depends upon the interdomain tilt between the FIII9 and FIII10 domains. Our data suggest that modulation of integrin binding by FIII9 may arise in part from its steric properties that determine accessibility of the RGD motif. These findings have wider implications for mechanisms of integrin-ligand binding in the physiological context.
LanguageEnglish
Pages5995-6003
Number of pages9
JournalJournal of Biological Chemistry
Volume279
DOIs
Publication statusPublished - 2004

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Fibronectins
Integrins
Ligands
Bioactivity
Extracellular Matrix
Modulation

Keywords

  • human fibronectin
  • signaling receptors
  • fibronectin

Cite this

Altroff, H., Schlinkert, R., Van Der Walle, C. F., Bernini, A., Campbell, I. D., Werner, J. M., & Mardon, H. J. (2004). Interdomain tilt angle determines integrin-dependent function of the ninth and tenth fIII domains of human fibronectin. Journal of Biological Chemistry, 279, 5995-6003. https://doi.org/10.1074/jbc.M406976200
Altroff, H. ; Schlinkert, R. ; Van Der Walle, C.F. ; Bernini, A. ; Campbell, I.D. ; Werner, J.M. ; Mardon, H.J. / Interdomain tilt angle determines integrin-dependent function of the ninth and tenth fIII domains of human fibronectin. In: Journal of Biological Chemistry. 2004 ; Vol. 279. pp. 5995-6003.
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Altroff, H, Schlinkert, R, Van Der Walle, CF, Bernini, A, Campbell, ID, Werner, JM & Mardon, HJ 2004, 'Interdomain tilt angle determines integrin-dependent function of the ninth and tenth fIII domains of human fibronectin' Journal of Biological Chemistry, vol. 279, pp. 5995-6003. https://doi.org/10.1074/jbc.M406976200

Interdomain tilt angle determines integrin-dependent function of the ninth and tenth fIII domains of human fibronectin. / Altroff, H.; Schlinkert, R.; Van Der Walle, C.F.; Bernini, A.; Campbell, I.D.; Werner, J.M.; Mardon, H.J.

In: Journal of Biological Chemistry, Vol. 279, 2004, p. 5995-6003.

Research output: Contribution to journalArticle

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T1 - Interdomain tilt angle determines integrin-dependent function of the ninth and tenth fIII domains of human fibronectin

AU - Altroff, H.

AU - Schlinkert, R.

AU - Van Der Walle, C.F.

AU - Bernini, A.

AU - Campbell, I.D.

AU - Werner, J.M.

AU - Mardon, H.J.

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N2 - Integrins are an important family of signaling receptors that mediate diverse cellular processes. The binding of the abundant extracellular matrix ligand fibronectin to integrins α5β1 and αvβ3 is known to depend upon the Arg-Gly-Asp (RGD) motif on the tenth fibronectin FIII domain. The adjacent ninth FIII domain provides a synergistic effect on RGD-mediated integrin α5β1 binding and downstream function. The precise molecular basis of this synergy remains elusive. Here we have dissected further the function of FIII9 in integrin binding by analyzing the biological activity of the FIII9-10 interdomain interface variants and by determining their structural and dynamic properties in solution. We demonstrate that the contribution of FIII9 to both α5β1 and αvβ3 binding and downstream function critically depends upon the interdomain tilt between the FIII9 and FIII10 domains. Our data suggest that modulation of integrin binding by FIII9 may arise in part from its steric properties that determine accessibility of the RGD motif. These findings have wider implications for mechanisms of integrin-ligand binding in the physiological context.

AB - Integrins are an important family of signaling receptors that mediate diverse cellular processes. The binding of the abundant extracellular matrix ligand fibronectin to integrins α5β1 and αvβ3 is known to depend upon the Arg-Gly-Asp (RGD) motif on the tenth fibronectin FIII domain. The adjacent ninth FIII domain provides a synergistic effect on RGD-mediated integrin α5β1 binding and downstream function. The precise molecular basis of this synergy remains elusive. Here we have dissected further the function of FIII9 in integrin binding by analyzing the biological activity of the FIII9-10 interdomain interface variants and by determining their structural and dynamic properties in solution. We demonstrate that the contribution of FIII9 to both α5β1 and αvβ3 binding and downstream function critically depends upon the interdomain tilt between the FIII9 and FIII10 domains. Our data suggest that modulation of integrin binding by FIII9 may arise in part from its steric properties that determine accessibility of the RGD motif. These findings have wider implications for mechanisms of integrin-ligand binding in the physiological context.

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