The structure of an integrin/talin complex reveals the basis of inside-out signal transduction

Abstract

Fundamental to cell adhesion and migration, integrins are large heterodimeric membrane proteins that uniquely mediate inside-out signal transduction, whereby adhesion to the extracellular matrix is activated from within the cell by direct binding of talin to the cytoplasmic tail of the b integrin subunit. Here, we report the first structure of talin bound to an authentic full-length b integrin tail. Using biophysical and whole cell measurements, we show that a specific ionic interaction between the talin F3 domain and the membrane-proximal helix of the b tail disrupts an integrin a/b salt bridge that helps maintain the integrin inactive state. Second, we identify a positively charged surface on the talin F2 domain that precisely orients talin to disrupt the heterodimeric integrin transmembrane (TM) complex. These results show key structural features that explain the ability of talin to mediate inside-out TM signalling.

The tale of two talins – two isoforms to fine‐tune integrin signalling

“…Validation of the conserved hydrophobic cores of these domains and comparison of the modelled F2F3 region of talin2 with the known structure 52 confirmed the reliability of this modelling approach. The domain boundaries of talin1 and talin2 are shown in Fig.…”

“…The other head subdomains achieve this by interaction with phosphoinositides such as PtdIns(4,5)P 2 (PIP2) in the plasma membrane; a basic surface on the F2 subdomain mediates interaction with the plasma membrane, which applies torque on the integrin to stabilise the active conformation 52, 56, 57. In addition, the F1 subdomain contains a large (~ 30aa) unstructured insertion, the F1‐loop, which, via a cluster of positively charged residues, interacts with PIP2 and is essential for integrin activation 58.…”

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

“…However, we found that binding of MDGI to integrin correlates with reduced activity. Recent models display the a-subunit in relatively close proximity of the bulky talin head binding to the b-tail (Anthis et al, 2009). Using molecular modeling, we investigated how MDGI could influence talin binding to the b-tail.…”

“…Conversely, the possible involvement of integrin a-subunits in integrin activity regulation has been poorly characterized apart from the role of positively charged residue(s) in integrin a-subunit, which contribute to a salt bridge involved in maintaining integrins in an inactive conformation (Anthis et al, 2009). Here, we present data of a novel integrin asubunit-binding protein, MDGI, which interacts directly with several a-integrins and inhibits integrin activity in cells.…”

“…Either ligand binding to the extracellular domain of the integrin or regulator binding to the intracellular tail of the integrin can activate integrin and shift the conformation to the extended high-affinity state (reviewed in Legate et al, 2009). Separation of cytoplasmic a-and b-tails is associated with the final step in integrin activation, which is supported by binding of the talin head domain to the cytoplasmic btail (Anthis et al, 2009). However, talin binding alone may not be sufficient as members of the kindlin family interact with b-tails and cooperate with talin in integrin activation (reviewed in Kloeker et al, 2004;Shi et al, 2007;Bo¨ttcher et al, 2009).…”