Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation

Liang Zhu, Jun Yang, Thomas Bromberger, Ashley Holly, Fan Lu, Huan Liu, Kevin Sun, Sarah Klapproth, Jamila Hirbawi, Tatiana V. Byzova, Edward F. Plow, Markus Moser () and Jun Qin ()
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Liang Zhu: Lerner Research Institute, Cleveland Clinic
Jun Yang: Lerner Research Institute, Cleveland Clinic
Thomas Bromberger: Department of Molecular Medicine
Ashley Holly: Lerner Research Institute, Cleveland Clinic
Fan Lu: Lerner Research Institute, Cleveland Clinic
Huan Liu: Lerner Research Institute, Cleveland Clinic
Kevin Sun: Lerner Research Institute, Cleveland Clinic
Sarah Klapproth: Department of Molecular Medicine
Jamila Hirbawi: Lerner Research Institute, Cleveland Clinic
Tatiana V. Byzova: Lerner Research Institute, Cleveland Clinic
Edward F. Plow: Lerner Research Institute, Cleveland Clinic
Markus Moser: Department of Molecular Medicine
Jun Qin: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Activation of transmembrane receptor integrin by talin is essential for inducing cell adhesion. However, the pathway that recruits talin to the membrane, which critically controls talin’s action, remains elusive. Membrane-anchored mammalian small GTPase Rap1 is known to bind talin-F0 domain but the binding was shown to be weak and thus hardly studied. Here we show structurally that talin-F0 binds to human Rap1b like canonical Rap1 effectors despite little sequence homology, and disruption of the binding strongly impairs integrin activation, cell adhesion, and cell spreading. Furthermore, while being weak in conventional binary binding conditions, the Rap1b/talin interaction becomes strong upon attachment of activated Rap1b to vesicular membranes that mimic the agonist-induced microenvironment. These data identify a crucial Rap1-mediated membrane-targeting mechanism for talin to activate integrin. They further broadly caution the analyses of weak protein–protein interactions that may be pivotal for function but neglected in the absence of specific cellular microenvironments.

Date: 2017
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DOI: 10.1038/s41467-017-01822-8

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