CASK Functions as a Mg2+-independent neurexin kinase.

TitleCASK Functions as a Mg2+-independent neurexin kinase.
Publication TypeJournal Article
Year of Publication2008
AuthorsMukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Südhof TC, Wahl MC
JournalCell
Volume133
Issue2
Pagination328-39
Date Published2008 Apr 18
ISSN1097-4172
KeywordsAnimals, Cell Line, Cells, Cultured, Crystallography, X-Ray, Glycoproteins, Guanylate Kinases, Humans, Magnesium, Mice, Models, Molecular, Neurons, Neuropeptides, Nucleotides, Protein Binding, Protein Structure, Tertiary, Rats, Sequence Homology, Amino Acid
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.

DOI10.1016/j.cell.2008.02.036
Alternate JournalCell
PubMed ID18423203
PubMed Central IDPMC3640377
Grant ListR37 MH052804 / MH / NIMH NIH HHS / United States
R37 MH052804-08 / MH / NIMH NIH HHS / United States
R37 MH52804-08 / MH / NIMH NIH HHS / United States