Complete integrin headpiece opening in eight steps

Abstract

Crystals soaked with RGD peptides reveal six intermediate conformational states between the closed and higher affinity, fully open state of the integrin αIIbβ3 headpiece.

Leukocyte integrin α L β 2 headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

“…Recently, higher resolution structures revealed the complete shape-shifting process for α IIb β 3 from closed to open with six intermediate, structurally defined steps (27). Examination of these structures for a contact similar to that found here in β 2 integrins shows that in α IIb β 3 opening, Tyr-122 in SDL1 maintains van der Waals contact with Met-180 in SDL2 (Fig.…”

“…Between the closed and open conformations, a 1.5 Å motion at the Tyr-122 backbone in SDL1 is associated with a 1.8 Å movement at the Met-180 backbone in SDL2. Although SDL2 does not contact peptide ligands soaked into α V β 3 or α IIb β 3 crystals (27,29,30), SDL2 might contact macromolecular ligands of these integrins. The similarity in concerted SDL1 and SDL2 movements in β 2 and β 3 integrins suggests that this mechanism for transmitting allostery between ligand-binding loops in integrins may hold for the half of integrin β subunits that have an equivalent Tyr residue in SDL1 and that include βI domains that bind both internal and external ligands.…”

“…Among the three βI domain specificitydetermining loops (SDLs), SDL1 contains the Asp-X-Ser-X-Ser MIDAS binding motif and ADMIDAS-coordinating residues in the β1-α1 loop and α1-helix, which move toward the ligand in transition from the closed to open βI domain conformations (27). Partial SDL1 movements toward the open conformation (intermediate conformations) are also induced when the ligand is soaked in or the internal ligand binds to integrins that are otherwise restrained in closed or bent conformations by crystal lattice contacts (16,27). Interestingly, comparison of our high-resolution α L β 2 headpiece structures to the 2.75 Å internally liganded intermediate "cocked" α X β 2 structure (16) now reveals substantial movement of SDL2 in addition to SDL1 in the intermediate conformation (Fig.…”

“…This coding sequence was followed by a 3C-protease site, the ACID coiled-coil, strep-tactin tag, and His 6 tag (27). β 2 -subunit mature residues Q1-E460 followed by a 3C-protease site, the BASE coiled-coil, strepavidin binding peptide, and His 6 tag were inserted into vector ET1 (31).…”

Atypical interactions of integrin α V β 8 with pro-TGF-β1

“…Physiologically, it appears that Mg 2+ is bound to the MIDAS and that Ca 2+ is bound to the SyMBS and ADMIDAS. Mn 2+ can replace the metals at all three sites (22,23). In conformational change from closed to open, the ADMIDAS metal ion moves ∼6 Å toward the MIDAS, and its coordination sphere alters from pentagonal bipyramidal that favors Ca 2+ to octahedral that favors Mn 2+ and Mg 2+ (23,24).…”