title: CASK Functions as a Mg2+-independent neurexin kinase.
abstract: CASK is a unique MAGUK protein that contains an N-terminal CaM-kinase domain besides the typical MAGUK domains. The CASK CaM-kinase domain is presumed to be a catalytically inactive pseudokinase because it lacks the canonical DFG motif required for Mg2+ binding that is thought to be indispensable for kinase activity. Here we show, however, that CASK functions as an active protein kinase even without Mg2+ binding. High-resolution crystal structures reveal that the CASK CaM-kinase domain adopts a constitutively active conformation that binds ATP and catalyzes phosphotransfer without Mg2+. The CASK CaM-kinase domain phosphorylates itself and at least one physiological interactor, the synaptic protein neurexin-1, to which CASK is recruited via its PDZ domain. Thus, our data indicate that CASK combines the scaffolding activity of MAGUKs with an unusual kinase activity that phosphorylates substrates recuited by the scaffolding activity. Moreover, our study suggests that other pseudokinases (10% of the kinome) could also be catalytically active.
authors.affiliation: Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9111, USA. konark.mukherjee@utsouthwestern.edu
authors.forename: Konark
authors.initials: K
authors.lastname: Mukherjee
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.forename: Gleb P
authors.initials: GP
authors.lastname: Bourenkov
authors.forename: Reinhard
authors.initials: R
authors.lastname: Jahn
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Markus C
authors.initials: MC
authors.lastname: Wahl
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000378:metabolism*; D051528:Guanylate Kinases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D006023:Glycoproteins; D009479:Neuropeptides; D009711:Nucleotides; C112162:neurexophilin; C106868:CASK kinases; D051528:Guanylate Kinases; D008274:Magnesium