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PDBsum entry 3c0h
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References listed in PDB file
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Key reference
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Title
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Cask functions as a mg2+-Independent neurexin kinase.
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Authors
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K.Mukherjee,
M.Sharma,
H.Urlaub,
G.P.Bourenkov,
R.Jahn,
T.C.Südhof,
M.C.Wahl.
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Ref.
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Cell, 2008,
133,
328-339.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1. Structure of the CASK CaM-Kinase Domain
(A and
B) Ribbon diagrams depicting the overall fold of the CASK
CaM-kinase domain in a complex with 3′-AMP (orthorhombic form,
A; see Figure S3 for the triclinic form) or AMPPNP (triclinic
form, B).
(C and D) Ribbon diagrams of rat CaMKI (C;
Goldberg et al., 1996; PDB ID: 1A06) and rat DAPK1 in a complex
with Mn^2+-AMPPNP (D; Tereshko et al., 2001; PDB ID: 1IG1).
All structures are shown in the same orientation with the
N-terminal lobes (dark gray) at the top and the C-terminal lobes
(light gray) at the bottom. Specific structural elements are
color-coded: portion of the glycine-rich loop (GR-loop) = brown;
catalytic loop (C-loop) = yellow; D/GFG of the Mg^2+ binding
loop = orange (the third residue is disordered in the CaMKI
structure); activation segment = green; C-terminal
Ca^2+/CaM-binding segment (CaM-segment) = red. Bound nucleotides
in (A) (3′-AMP), (B) (5′-AMP portion of AMPPNP), and (D)
(AMPPNP) are shown in ball-and-sticks.
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Figure 7.
Figure 7. Model of Neurexin Phosphorylation by CASK
Neurexin (Nx) and neuroligin (NL) are thought to interact
extracellularly with each other across the synaptic cleft and to
associate intracellularly with the MAGUKs CASK and PSD-95,
respectively. CASK is recruited to the cytosolic C-tail of
neurexin via the CASK PDZ domain and phosphorylates the neurexin
C-terminal tail. Protein 4.1, which binds the C-tail of neurexin
as well as CASK, nucleates actin filaments, modulating the
presynaptic cytoskeleton. The red indicator depicts the
inhibition of CASK CaM-kinase activity due to an increase in
cytosolic divalent cations.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2008,
133,
328-339)
copyright 2008.
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