A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion.
The activation of heterodimeric (α/β) integrin transmembrane receptors by cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent processes, including blood coagulation, tissue remodeling, and cancer metastasis. This process is triggered by the coincident binding of N-terminal FERM (four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner membrane surface and integrin β cytoplasmic tail, but how these binding events are spatiotemporally regulated remains obscure. Here we report the crystal structure of a dormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a key integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure also reveals a distinct negatively charged surface on talin-RS that electrostatically hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin is consistent with the biochemical and functional data, but differs significantly from a previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate (PIP2) - a known talin activator, membrane strongly attracts a positively charged surface on talin-FERM and simultaneously repels the negatively charged surface on talin-RS. Such an electrostatic "pull-push" process promotes the relief of the dual inhibition of talin-FERM, which differs from the classic "steric clash" model for conventional PIP2-induced FERM domain activation. These data therefore unravel a new type of membrane-dependent FERM domain regulation and illustrate how it mediates the talin on/off switches to regulate integrin transmembrane signaling and cell adhesion.
Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Xianqiang
X
Song
Jun
J
Yang
Jamila
J
Hirbawi
Sheng
S
Ye
H Dhanuja
HD
Perera
Esen
E
Goksoy
Pallavi
P
Dwivedi
Edward F
EF
Plow
Rongguang
R
Zhang
Jun
J
Qin
D001665:Binding Sites; D002448:Cell Adhesion; D002450:Cell Communication; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism*; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D055672:Static Electricity; D016608:Talin / Q000737:chemistry* / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D039641:Integrin beta Chains; D016023:Integrins; D008024:Ligands; D019269:Phosphatidylinositol 4,5-Diphosphate; D011956:Receptors, Cell Surface; D016608:Talin