Although integrins bind to a structurally diverse range of ligands, most of these ligands contain the sequence Arg–Gly–Asp (RGD). The structural basis for this cation-dependent interaction has been unclear, but now, in Science, Arnaout and colleagues report the crystal structure of the extracellular segment of integrin αVβ3 in complex with an RGD ligand.
Integrins are composed of an alpha (α)and beta (β)subunit — both type I membrane proteins with large extracellular domains — and fall into two classes depending on the presence or absence of an αA domain. Studies on the structure of αA have previously shown that a metal-ion-dependent adhesion site (MIDAS) at the ligand-binding interface is required for ligand interactions with αA-containing integrins. In αVβ3, which lacks αA, Arnaout and co-workers found that ligand binding is mediated by an αA-like βA domain in β3. Surprisingly, βA acquires two cations on complex formation — one in MIDAS and another in a ligand-associated metal-binding site (LIMBS). They propose that LIMBS, which does not directly contact RGD, stabilizes the ligand-binding surface.
The authors found that RGD binds at the major interface between αV and β3, and induces both tertiary and quaternary structural changes, which probably represent “a minimalist view” of the changes in integrins that are required for cell signalling. Although the ligand used here was synthetic, its RGD motif is almost conformationally identical to that present in a known natural ligand, which indicates that this structure can be used to understand integrin interactions with other RGD-containing ligands.
ORIGINAL RESEARCH PAPER
Xiong, J.-P. et al. Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg–Gly–Asp ligand. Science 296, 151–155 (2002)
Plow, E. F. et al. Ligand binding to integrins. J. Biol. Chem. 275, 21785–21788 (2000)
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Smallridge, R. The MIDAS touch. Nat Rev Mol Cell Biol 3, 313 (2002). https://doi.org/10.1038/nrm821