Structure Watch

A powerful weak handshake

Integrins are heterodimeric (α, β) cell-surface receptors that mediate interactions between cells, and between cells and the extracellular matrix. The α and β subunits both have a small cytoplasmic tail, a transmembrane domain and a large extracellular domain, and the extracellular domains form sites that bind numerous ligands. Activation of the ligand-binding function, however, only occurs on receipt of an 'inside?out' signal from the cytoplasmic tails ? a process that has remained poorly understood. Now, though, two papers in Cell provide new insights.

In the first paper, Qin and colleagues present the NMR structure of the cytoplasmic face of the integrin α_IIbβ₃, which shows a ?weak handshake? between the membrane-proximal helices of the α_IIb and β₃ cytoplasmic tails. The residues that mediate this interaction are highly conserved in all integrins, which indicates that this interaction and its functions are probably conserved. When the authors studied cytoplasmic-tail point mutations that are known to produce a constitutively active form of α_IIbβ₃, they found that they disrupted the tail interface. In addition, they showed that talin ? a cytoskeletal protein that activates α_IIbβ₃ in vivo by binding to the β₃ tail ? seems to compete with the α_IIb tail for binding to β₃, which disrupts the tail interface. These results have provided ?a structural mechanism by which a handshake between the α and the β cytoplasmic tails restrains the integrin in a resting state and unclasping of this interaction triggers the inside-out conformational signal that leads to receptor activation?.

The big picture

In the other Cell paper, Springer and colleagues used techniques including electron microscopy to study the integrin-structure rearrangements that are involved in 'outside?in' and 'inside?out' signalling and that control the affinity of integrins for their ligands.

The authors studied the extracellular region of α_Vβ₃ in two forms ? 'clasped' (α and β subunits were linked through a carboxy-terminal 'clasp' to mimic the interaction of the α/β cytoplasmic tails (see above)) and 'unclasped'. They saw that integrins have, at the least, three conformational states ? bent (V-shaped), extended with a closed headpiece and extended with an open headpiece. They showed that the bent conformation, which was previously observed in a crystal structure, is physiologically relevant, and has a low ligand-binding affinity. The clasped form of α_Vβ₃ favours this bent conformation, which fits with the observation that α/β cytoplasmic-tail interactions restrain integrins in an inactive form (described above). On addition of either a high-affinity ligand-mimetic peptide or Mn²⁺ (which activates all integrins by binding to the extracellular region) to α_Vβ₃, Springer and co-workers observed a ?switchblade-like opening? to the high-affinity extended conformer with the open headpiece. Unclasped α_Vβ₃ favours this conformation, which again concurs with the results described above. They propose that the extended conformer with the closed headpiece represents an intermediate conformation with an intermediate ligand-binding affinity. REFERENCES Vinogradova, O. et al. A structural mechanism of integrin αIIbβ3 ?inside-out? activation as regulated by its cytoplasmic face. Cell 110, 587?597 (2002) Takagi, J. et al. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599?611 (2002)