The structure of an integrin/talin complex reveals the basis of inside-out signal transduction.
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 beta integrin subunit. Here, we report the first structure of talin bound to an authentic full-length beta 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 beta tail disrupts an integrin alpha/beta 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.
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. nick.anthis@gmail.com
Nicholas J
NJ
Anthis
Kate L
KL
Wegener
Feng
F
Ye
Chungho
C
Kim
Benjamin T
BT
Goult
Edward D
ED
Lowe
Ioannis
I
Vakonakis
Neil
N
Bate
David R
DR
Critchley
Mark H
MH
Ginsberg
Iain D
ID
Campbell
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D016023:Integrins / Q000737:chemistry* / Q000378:metabolism; D046911:Macromolecular Substances / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D016608:Talin / Q000737:chemistry* / Q000378:metabolism
D016023:Integrins; D046911:Macromolecular Substances; D016608:Talin