LIG_CaMK_CASK_1

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).