Complex of integrin B-subunit cytoplasmic domain and talin F3 domain
Gallus gallus domesticus(chicken)
Integrins are cell-surface proteins. They play roles in adhesion with extracellular matrix and signal transduction between cells. They consist of membrane-spanning heterodimes α and β subunits, both of which typically comprise a short cytoplasmic domain, a transmembrane domain, and a large extracellular domain. (Fig.1). Integrins are expressed with their extracellular domains in a default low-affinity ligand-binding state. However, activation of cytoplasmic domain results in the separation of transmembrane domains of α and β subunit. As this structural change spreads to the extracellular domain, the extracellular domain transforms to a high-affinity state, and can bind to extracellular matrix. It is thought that the binding of talin to the integrin β-subunit cytoplasmic tail(β-integrin tail) is the final step in the activation process.
However, the detailed mechanism of the activation is still unknown. Talin consists of a large C-terminal domain that contains bundles of α helices and an N-terminal FERM domain with three subdomains: F1, F2, and F3. The F3 subdomain contains the highest affinity integrin-binding site(PTB site) for β-integrin tail. Several other proteins which work with the PTB site exist, and they can bind to β-integrin tail in a similar fashion to talin. But, only talin is able to activate the integrin. In order to solve an integrin activation mechanism that is unique to talin, the complex structure of β-integrin tail / talin F3 was determined. Thorough understanding of the integrin activation mechanism should contribute to the cell engineering.
(*) In mammals, there are 18 identified α subunits and 8 β subunits that combine to form 24 distinct heterodimers.
What is shown here is a complex of β-integrin tail / talin F3 determined by NMR. (Fig.2). β-integrin tail bind to talin F3 with two regions. One is MP (membrane proximal) region near the membrane. The other is MD (membrane distal) region distant from the membrane. The interactions between β-integrin tail MD region and talin F3 has been already revealed by X-ray crystallographic analysis. - xPSSS:1MK7. The complex obtained this time revealed important contacts between the β-integrin tail MP region and talin F3. The loop between S1 and S2 of talin F3 is stiffened by binding to the MP region. (Fig.3). When any of 6 residues(F3:L325, S365, S379, Q381, MP:F727, F730) which contribute to the F3-MP interactions was mutated, although talin can bind to MD region, the activation ablility of integrin decreased. And, it was identified that the other protein with PTB site has a very short S1-S2 loop. Thus, the interactions between S1-S2 loop of talin F3 and MP region are important for integrin activation.
K322 in the S1-S2 loop points toward the membrane. When this residue was mutated, activation of integrin was also inhibited. F3-membrane interactions, together with F3-MP interactions, make significanti contributions to the integrin activation. Summarizing all the points above, it is hypothesized that activation of integrin by talin F3 is performed through the process shown below. (Fig.4).
Protein Data Bank (PDB)
Wegener, K.L. Partridge, A.W. Han, J. Pickford, A.R. Liddington, R.C. Ginsberg, M.H. Campbell, I.D.; "Structural basis of integrin activation by talin"; CELL(CAMBRIDGE,MASS.); (2007) 128:171-182 PubMed:17218263.
author: Jun-ichi Ito