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Published 28 March 2005. doi:10.1083/jcb.200410068
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 7, 1109-1118
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Article

Three-dimensional EM structure of the ectodomain of integrin {alpha}Vß3 in a complex with fibronectin



Brian D. Adair1, Jian-Ping Xiong3, Catherine Maddock4, Simon L. Goodman4, M. Amin Arnaout3, and Mark Yeager1,2

1 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, CA 92037
3 Structural Biology Program, Leukocyte Biology and Inflammation Program, Renal Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
4 Oncology Research, Merck KGaA, Darmstadt 64271, Germany

Correspondence to M.A. Arnaout: arnaout{at}receptor.mgh.harvard.edu; or M. Yeager: yeager{at}scripps.edu

Integrins are {alpha}ß heterodimeric cell surface receptors that mediate transmembrane signaling by binding extracellular and cytoplasmic ligands. The ectodomain of integrin {alpha}Vß3 crystallizes in a bent, genuflexed conformation considered to be inactive (unable to bind physiological ligands in solution) unless it is fully extended by activating stimuli. We generated a stable, soluble complex of the Mn2+-bound {alpha}Vß3 ectodomain with a fragment of fibronectin (FN) containing type III domains 7 to 10 and the EDB domain (FN7-EDB-10). Transmission electron microscopy and single particle image analysis were used to determine the three-dimensional structure of this complex. Most {alpha}Vß3 particles, whether unliganded or FN-bound, displayed compact, triangular shapes. A difference map comparing ligand-free and FN-bound {alpha}Vß3 revealed density that could accommodate the RGD-containing FN10 in proximity to the ligand-binding site of ß3, with FN9 just adjacent to the synergy site binding region of {alpha}V. We conclude that the ectodomain of {alpha}Vß3 manifests a bent conformation that is capable of stably binding a physiological ligand in solution.

Abbreviations used in this paper: 3D, three-dimensional; ßTD, ß-tail domain; FN, fibronectin; FSC, Fourier shell correlation; RFC, reference-free classification.


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