PDBsum entry 3c0h

Transferase

PDB id: 3c0h

Contents

Protein chains

300 a.a. *

Ligands

AMP ×2

Waters ×258

* Residue conservation analysis

PDB id:

3c0h

Name:

Transferase

Title:

Cask cam-kinase domain- amppnp complex, p1 form

Structure:

Peripheral plasma membrane protein cask. Chain: a, b. Fragment: cam-kinase domain. Synonym: hcask, calcium/calmodulin-dependent serine protein kinase, lin-2 homolog. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cask. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.

Resolution:

2.30Å R-factor: 0.191 R-free: 0.239

Authors:

M.C.Wahl

Key ref:

K.Mukherjee et al. (2008). CASK Functions as a Mg2+-independent neurexin kinase. Cell, 133, 328-339. PubMed id: 18423203 DOI: 10.1016/j.cell.2008.02.036

Date:

20-Jan-08 Release date: 29-Apr-08

Protein chains

O14936  (CSKP_HUMAN) -  Peripheral plasma membrane protein CASK from Homo sapiens

Seq: 926 a.a.

Struc: 300 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = AMP) matches with 85.19% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = AMP) matches with 85.19% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.cell.2008.02.036

Cell 133:328-339 (2008)

PubMed id: 18423203

CASK Functions as a Mg2+-independent neurexin kinase.

K.Mukherjee, M.Sharma, H.Urlaub, G.P.Bourenkov, R.Jahn, T.C.Südhof, M.C.Wahl.

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from Cell Press: Cell (2008, 133, 328-339) copyright 2008.

Figures were selected by an automated process.