Membrane-proximal α/β stalk interactions differentially regulate integrin activation

Tetsuji Kamata, Makoto Handa, Yukiko Sato, Yasuo Ikeda, Sadakazu Aiso

研究成果: Article

39 引用 (Scopus)

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The affinity of integrin-ligand interaction is regulated extracellularly by divalent cations and intracellularly by inside-out signaling. We report here that the extracellular, membrane-proximal α/β stalk interactions not only regulate cation-induced integrin activation but also play critical roles in propagating inside-out signaling. Two closely related integrins, αIIbβ3 and αVβ3, share high structural homology and bind to similar ligands in an RGD-dependent manner. Despite these structural and functional similarities, they exhibit distinct responses to Mn2+. Although αVβ3 showed robust ligand binding in the presence of Mn 2+, αIIbβ3 showed a limited increase but failed to achieve full activation. Swapping α stalk regions between αIIb and αV revealed that the α stalk, but not the ligand-binding head region, was responsible for the difference. A series of αIIb/αV domain-swapping chimeras were constructed to identify the responsible domain. Surprisingly, the minimum component required to render αIIbβ3 susceptible to Mn 2+ activation was the αV calf-2 domain, which does not contain any divalent cation-binding sites. The calf-2 domain makes interface with β epidermal growth factor 4 and β tail domain in three-dimensional structure. The effect of calf-2 domain swapping was partially reproduced by mutating the specific amino acid residues in the calf-2/epidermal growth factor 4-β tail domain interface. When this interface was constrained by an artificially introduced disulfide bridge, the Mn2+-induced αVβ3-fibrinogen interaction was significantly impaired. Notably, a similar disulfide bridge completely abrogated fibrinogen binding to αIIbβ3 when αIIbβ3 was activated by cytoplasmic tail truncation to mimic inside-out signaling. Thus, disruption/formation of the membrane-proximal α/β stalk interface may act as an on/off switch that triggers integrin-mediated bidirectional signaling.

元の言語English
ページ(範囲)24775-24783
ページ数9
ジャーナルJournal of Biological Chemistry
280
発行部数26
DOI
出版物ステータスPublished - 2005 7 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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