The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
CASK CaMK domain binding ligand motif
Functional site description:
The peripheral plasma membrane protein CASK (Calcium/calmodulin-dependent serine protein kinase CASK; Lin-2 homolog) is a scaffold protein that is involved in synapse formation and signal transduction. It belongs to the membrane-associated guanylate kinase (MAGUK) protein family and was found to be an essential protein in vertebrates. CASK is a multidomain protein comprising several protein interaction domains, including a PDZ, SH3, and calmodulin-dependent protein kinase (CaMK) domain, which collectively target CASK to its many binding partners and mediate complex assembly. The CaMK domain recognizes target proteins such as Caskin-1, Mint-1, and Liprin-alpha-2 through their CaMK-binding motif, which consists of a hydrophobic core and is situated within the largely unstructured CASK Interaction Domain (CID).
ELM Description:
The CASK-CaMK-binding motif mediates specific binding to the CaMK domain of the CASK protein. The motif is located in an unstructured region of CaMK-binding proteins and binds with an affinity in the low micromolar range (7.5 ┬ÁM for the motif of Caskin-1) (Stafford,2011). The motif contains an invariant Trp residue that it is inserted in a hydrophobic pocket on the surface of the CASK CaMK domain containing Val117 (6KMH). Furthermore, a Val or Ile residue adjacent to the Trp completes the hydrophobic core of the motif. In addition to this, the motifs contain either a mandatory Arginine or Histidine in the last position, in order to form an H bond with a water molecule (conserved in all crystal structures) and to interact with His287 in the CaMK domain. In addition, mutation and deletion studies showed that loss of the N-terminal acidic residue or the invariant C-terminal basic Arg residue impairs the binding of the motif, indicating an involvement of these residues in the binding process (Stafford,2011). Several invertebrates, mainly insects, contain an alternative SP site instead of the conserved acidic residue at the N-terminus of the motif that binds via an H-bond to the backbone of the structure. This might represent a modification site for proline-directed kinases that would mimic an acidic residue after phosphorylation, which would allow regulated induction of motif binding. Binding of the motif might also be regulated by modification of the CaMK domain. Later studies on the CaMK domain of CASK refuted the assumption that it is a catalytically inactive pseudokinase: It was shown that the CaMK domain of CASK is capable of auto-phosphorylation at Ser151 and Ser155. As these residues lie spatially close to the predicted interaction site of the CaMK-binding motif, these modifications might modulate motif binding (Mukherjee,2008; Stafford,2011).
Pattern: [STED].{0,2}[IV]W[IVLM].[RHK]
Pattern Probability: 0.0000112
Present in taxon: Metazoa
Interaction Domains:
  • Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
  • Protein kinase domain (IPR000719) Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases (Stochiometry: 1 : 1)
o See 7 Instances for LIG_CaMK_CASK_1
o Abstract
The peripheral plasma membrane protein CASK/LIN2 (Calcium/calmodulin-dependent serine protein kinase, CSKP_HUMAN; CSKP_RAT) is a scaffold protein that belongs to the membrane-associated guanylate kinase (MAGUK) protein family and is conserved in vertebrates and invertebrates. In vertebrates, CASK is an essential protein as gene knockout leads to perinatal death in mice (Atasoy,2007, however for invertebrates the gene seems to be dispensable (LaConte,2013). There are several studies that show how CASK gene mutations are related both to Microcephaly with pontine and cerebellar hypoplasia (MICPCH), mostly in females, and also to X-linked intellectual disability (XLID)
(Moog and Kutsch, 2013). Because the gene is located in the X chromosome, both disorders are more frequent in females (Najm,2008; Bencsik,2019; Moog,2015) and phenotypes can vary between the genders. CASK has low tissue specificity but shows high expression in neuronal tissue where its function seems most critical: here it is mainly localized to the pre-and postsynaptic membranes. In this context, CASK was found to regulate both pre-and postsynaptic processes including the formation of presynaptic termini, neurotransmitter release, the maintenance of the morphology of the dendritic spines, and the regulation and localization of ion channels. In addition, CASK contributes to the establishment of cell polarity and can migrate to the nucleus, where it is also involved in the regulation of gene expression, for instance via guanylate kinase domain binding of the T-box transcription factor Tbr-1 (Hsueh,2000; Hsueh,2006). It is also involved in insulin secretion and vesicle transport (Zhang,2020).
CASK is a multidomain protein that contains a PDZ domain (PF00595), an SH3 domain (PF07653), and a guanylate kinase (GK) domain (PF00625). The presence of two additional L27 domains (PF02828) is characteristic of the p55 subfamily (Hsueh,2006). In addition, CASK contains a unique N-terminal calmodulin-dependent protein kinase (CaMK) domain (PF00069; 3MFR; Mukherjee,2010). Because it lacks the Mg2+ binding motif, which is considered to be required for the catalytic activity of protein kinases, the CaMK domain of CASK was regarded as a non-active pseudokinase involved only in non-catalytic protein-protein interactions. However, later studies refuted this by showing CaMK auto-phosphorylation and phosphorylation of the membrane adhesion protein Neurexin-1 (Q9ULB1) by CASK, indicating a further involvement of this protein in phosphorylation processes (Mukherjee,2010). These different interaction domains, for which different binding partners have been identified, allow CASK to bind multiple targets simultaneously and serve as a scaffold protein that mediates the assembly of protein complexes.
A validated binding partner of the CASK CaMK domain is Mint-1/APBA1 (Neuronal Munc18-1-interacting protein 1, Q02410), which, together with CASK and Veli (MALS/Lin-7) proteins, forms tripartite complexes that bind to the cytoplasmic tail of Neurexin-1 at pre- and postsynaptic sites (Hata,1996). The CASK-Veli-Mint-1 complex is involved in the regulation of synaptic signal transduction. At the presynapse, it forms a quadripartite complex with liprin-alpha-2 (Wei,2011) that plays a role in vesicular release (Olsen,2005), while at the postsynapse it directs the transport of NMDA receptors along microtubules (Setou,2000).
Regulation of CASK-Veli-Mint-1 complex assembly involves Caskin-1 (CASK-interacting protein 1, Q8WXD9). This brain-specific multidomain protein Caskin-1 competes with Mint-1 for binding to the CaMK domain of CASK and forms distinct tripartite complexes with CASK and Veli proteins to modulate the function of CASK (Tabuchi,2002). The competitive binding of Caskin-1 and Mint-1 to CASK depends on a common motif in the two competitors that binds to a hydrophobic pocket on the CaMK domain of CASK. The CaMK-binding motif is localized within the CASK interaction domain (CID) of the ligand proteins, an intrinsically unstructured region that was initially identified as a CaMK-binding domain in Mint-1 (Borg,1999). The TIAM-1 protein (T-lymphoma invasion and metastasis-inducing protein 1, Q13009) was found to contain a similar motif sequence and interact with CASK, which might be relevant considering its high expression level in brain tissue and overlapping functions with CASK, including dendritic spine development (Ehler,1997; Tolias,2007).
o 7 selected references:

o 12 GO-Terms:

o 7 Instances for LIG_CaMK_CASK_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O75334 PPFIA2
977 984 PTSRTPSGNVWVTHEEMENL TP 4 Homo sapiens (Human)
Q13009 TIAM1
1572 1578 LESASEEVIWVRREDFAPSR TP 2 Homo sapiens (Human)
Q8VHK2 Caskin1
374 379 GPSAPPEEIWVLRKPFAGGD TP 5 Rattus norvegicus (Norway rat)
374 379 GPSAPPEEIWVLRKPFAGGD TP 6 Homo sapiens (Human)
O35430 Apba1
378 384 TPDEPKEPIWVMRQDISPTR TP 13 Rattus norvegicus (Norway rat)
B2RUJ5 Apba1
381 387 TPDEPKEPIWVMRQDISPTR TP 8 Mus musculus (House mouse)
Q02410 APBA1
376 382 TPDEPKEPIWVMRQDISPTR TP 6 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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