title: Liprin-mediated large signaling complex organization revealed by the liprin-α/CASK and liprin-α/liprin-β complex structures.
abstract: 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-α2/CASK complex structure solved here reveals that the three SAM domains of liprin-α form an integrated supramodule that binds to the CASK kinase-like domain. As supported by biochemical and cellular studies, the interaction between liprin-α and CASK is unique to vertebrates, implying that the liprin-α/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-α. We also solved the liprin-α/liprin-β SAM domain complex structure, which uncovers the mechanism underlying liprin heterodimerizaion. Finally, formation of the CASK/liprin-α/liprin-β ternary complex suggests that liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities.
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Wei
authors.forename: Suilan
authors.initials: S
authors.lastname: Zheng
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Spangler
authors.forename: Cong
authors.initials: C
authors.lastname: Yu
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D051528:Guanylate Kinases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017729:Presynaptic Terminals / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C470384:PPFIA2 protein, human; C449803:PPFIBP1 protein, human; C106868:CASK kinases; D051528:Guanylate Kinases