Liprin-Mediated Large Signaling Complex Organization Revealed by the Liprin-α/CASK and Liprin-α/Liprin-β Complex Structures

Liprins are highly conserved scaffold proteins that regulate cell adhesion, cell migration, and synapse development by binding to diverse target proteins. The molecular basis governing liprin/target interactions is poorly understood. The liprin-alpha 2/CASK complex structure solved here reveals that the three SAM domains of liprin-alpha form an integrated supramodule that binds to the CASK kinase-like domain. As supported by biochemical and cellular studies, the interaction between liprin-alpha and CASK is unique to vertebrates, implying that the liprin-alpha/CASK interaction is likely to regulate higher-order brain functions in mammals. Consistently, we demonstrate that three recently identified X-linked mental retardation mutants of CASK are defective in binding to liprin-alpha. We also solved the liprin-alpha/liprin-beta SAM domain complex structure, which uncovers the mechanism underlying liprin heterodimerizaion. Finally, formation of the CASK/liprin-alpha/liprin-beta ternary complex suggests that liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities.