Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MAGUK

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101711

Synonyms

Historical Background

Membrane-associated guanylate kinases (MAGUKs) are a family of proteins generally involved in scaffolding. Functions for these proteins have been described in diverse cellular processes such as epithelial polarity and maintenance, cell-cell communication, synapse physiology, cell polarity, and signal transduction (Oliva et al. 2012). The protein family is characterized by the presence of a guanylate kinase (GK) domain, homologous to the bacterial guanylate kinase enzyme involved in the transfer of a phosphate group from ATP to GMP, essential in GTP synthesis (Li and Yan 1996; Zhu et al. 2012). However, in the MAGUK family, this domain is enzymatically inactive and instead mediates protein-protein interactions.

The founder members of the MAGUK family are the postsynaptic density proteins of 95 KDa (PSD95), Zonula Occludens 1 (ZO1) and the Drosophila Discs Large (DLG). They share a similar structure with PDZ (PSD95, DLG, ZO1) domains, SH3 (SRC Homology 3 Domain), and GK domains and have been classified as belonging to the same family (Woods and Bryant 1993). Today the MAGUK family includes several subfamilies with two atypical members: the voltage-activated calcium channels beta subunit (CACNβ) that lacks the PDZ domain and the membrane-associated guanylate kinase inverted (MAGI) that lacks the SH3 domain. MAGUK functions have been described in diverse cell types, but all are involved in the organization of signal transduction complexes.

MAGUK Subfamilies

MAGUK proteins have been classified according to their domain structure and phylogenetic position. They are found in all metazoans, with subfamilies CARMA and MPP1 found only in vertebrates (for a detailed phylogenetic analysis see de Mendoza et al. (2010)). The accepted subfamily classification is given in Fig. 1, listed according to the number of different domains that each subfamily possesses, starting with the calcium channel-β subunit (CACNβ) subfamily, which has the simplest structure having only SH3 and GK domains. The MPP1 subfamily incorporates the PDZ domain, completing the basic core of the MAGUK family. Next is the caspase recruitment domain (CARMA) subfamily that represents proteins having all of the key domains of the family but with an additional CARD domain. This is followed by the DLG family, which includes genes DLG1–4. We have listed DLG2 separately to highlight the fact that it does not display a L27 (LIN2 and LIN7) domain in its gene structure, differing thus from DLG1, 3, and 4, which do have a L27 domain in the gene structure, which can be found as alternatively spliced proteins (Chetkovich et al. 2002). The list continues with the subfamily that includes the genes MPP2–7, which add two L27 domains to the basic protein structure of MPP1, followed by the calcium/calmodulin-dependent protein kinase (CASK) subfamily that has an additional CaM kinase domain at the N-terminal end of the protein. The list goes on to include the DLG5 subfamily that includes a CARD domain, thus differing in structure from the other DLG proteins. The next subfamily is represented by the Zona Occludens (ZO) proteins that include ZO1–3. We depict ZO1 separately to show that it displays an extra ZU5 (Zona Occludens and UNC5) domain not present in the other two genes. The last member on the list is the atypical membrane-associated guanylate kinase with inverted repeat (MAGI), which possesses two WW domains that replace the characteristic SH3 domain and has the GK domain at the N-terminal end of the protein instead of at the C-terminus.
MAGUK, Fig. 1

Representative domain structure of the MAGUK subfamilies based on their protein domain composition. Each domain is depicted in a different color and shape. The list start from the simplest structured MAGUK, the beta subunit of the voltage-activated calcium channel (CACNB). MPP membrane palmitoylated protein, CARMA CARD-containing MAGUK, DLG discs large, CASK calcium/calmodulin-dependent serine protein kinase, ZO zona occludens, MAGI membrane-associated gunylate kinase inverted

MAGUK Structural Domains

GK and SH3 Domains

Canonical GK domains are highly conserved from yeast to human, playing important roles in GMP/cGMP metabolism. The MAGUKs GK domain shares around 40% sequence identity with the yeast guanylate kinase, but binds GMP and ATP very weakly and is therefore considered to have no relevant enzyme activity (Zhu et al. 2012). The MAGUKs GK domain has evolved instead as a protein-protein interaction motif characterized by binding phosphoproteins. Several MAGUK protein partners also bind through this domain. For instance, the SH3-GK tandem of SAP97 binds to a phospho-peptide derived from the LGN protein, a molecule involved in the regulation of the mitotic spindle (Zhu et al. 2011).

SH3 domains usually bind proline-rich sequences, although the MAGUK SH3 domain does not interact with these kinds of motifs. It has been shown that MAGUK SH3 and GK domains form a supramodule through intramolecular interactions (McGee et al. 2001). Furthermore, formation of this module has been shown to provide specificity for binding of the PDZ domains in the protein that can be highly promiscuous in vitro (Zhu et al. 2016). The presence of this module has also been shown to be important in vivo, in flies, for correct embryonic development (Woods et al. 1996). In vertebrates PSD95 binds to Kv1.4 potassium channel through their PDZ1–2 domains, and interestingly mutations that affect SH3-GK intramolecular interactions display defective Kv1.4 clustering (Shin et al. 2000).

L27 Domain

The L27 domain is present in some MAGUK proteins (CASK, DLG1, MPP2–7) in the N-terminal sequence. The domain is named after C. elegans proteins Lin2 and Lin7 that share this domain. The L27 domain is also involved in the formation of multiprotein complexes through binding to other L27 domains that are either homomeric or heteromeric. For example, in Drosophila neuromuscular junction (NMJ), it has been shown that a complex formed by DLGS97 (a fly ortholog of SAP97) DLin7 and Metro (an MPP-like MAGUK protein) is mediated by the interaction between the L27 domains of the three proteins. This complex is involved in the regulation of the size of glutamate receptor fields (Bachmann et al. 2010).

PDZ Domains

PDZ domains are among the most common protein-protein interaction modules. They have a length of about 100 aminoacids and are often involved in the organization of signal transduction cascades associated with membrane receptors or channels (Kim and Sheng 2004). In general, they bind to a short stretch of aminoacid residues with a specific sequence at the carboxyl-terminus of partner proteins, although they can also bind to internal sequences. Three types of PDZ domains that bind to different motifs have been described (Harris and Lim 2001). While DLG1–4 has only type I PDZ domains, CASK, some members of the MPP subfamily and MAGI, have type II PDZ domains. The structure of the complex between PDZ and the binding sequences has been determined for a number of partners (Zhu et al. 2016).

An example of how MAGUK proteins interact with partners through PDZ domains is the interaction of DLG4 (PSD95) with Shaker-type K+ channels and NMDA glutamate receptors that through its first two PDZ domains interact with specific-binding motifs in the C-terminus of these two receptors, participating in the clustering of these proteins at postsynaptic sites in the cell (Kim et al. 1995; Niethammer et al. 1996).

MAGUK Regulation

Since MAGUKs have multiple protein-protein interaction domains, they facilitate the assembly of large complexes in several contexts. These complexes change dynamically in their composition and localization on exposure to external signals.

MAGUK proteins have been shown to be regulated by palmitoylation, alternative splicing, phosphorylation, and nuclear translocation (Funke et al. 2005).

Palmitoylation occurs when palmitate fatty acid is added to a cysteine residue of a protein. The hydrophobic nature of this modification means that it can alter protein interactions. This posttranslational modification of PSD95 plays a role in the binding of PSD95 to ion channels such as the Kv 1.4 potassium channel (Topinka and Bredt 1998; Funke et al. 2005).

Alternative splicing can modify the number or quality of protein structural domains and therefore the binding specificity, localization, or function of a protein. A striking case is the alternative splicing of the first translated exon in members of the DLG family: PSD95, PSD93, and SAP97 can undergo this modification, which replaces the L27 domain (β-isoforms) by the palmitoylated motif (α-isoforms). Thus, for instance, modulating the binding of PSD95 to CASK, which only happens in the presence of the L27 domain (Chetkovich et al. 2002; Oliva et al. 2012).

In Drosophila, DLG is regulated by a CaM Kinase II (CAMKII)-mediated phosphorylation and this modification is required for synapse formation in the NMJ (Koh et al. 1999).

Finally, although MAGUKs usually bind to cytoplasmic and membrane proteins, at least some of them can also translocate to the nucleus and act as transcription factors. Thus, in mammals, CASK binds to the transcription factor Tbr-1 and the complex activates transcription of Tbr-1 targets (Hsueh et al. 2000).

MAGUKs in Synapse Formation and Function

Neuronal communication is mainly through chemical synapses in which presynaptic and postsynaptic sites are opposed to each other. Neurotransmitters are released from the presynaptic neuron into the synaptic cleft and then bind to specific receptors on the postsynaptic neuron. It is now well known that MAGUKs are required for the organization of both these compartments and that they have a scaffolding role for the anchoring of receptors, ion channels, and other molecules (Oliva et al. 2012; Zhu et al. 2016). It is known for instance that a specialized region of the postsynaptic structure, the postsynaptic density (PSD) is composed of thousands of different proteins (Sheng and Hoogenraad 2007). Six percent of the PSD is made of scaffold proteins, and of these MAGUK molecules make up a significant contribution to the total. In mammalian neurons, PSD95 is the most abundant scaffold protein. It is mainly postsynaptic and involved in the clustering and abundance of glutamate receptors (Chen et al. 2015). PSD95 binds directly through its PDZ domains to the NMDA-type glutamate receptor and through the protein Stargazin to AMPA-type glutamate receptors (Oliva et al. 2012). As well as their known role in the organization of the postsynaptic density of the DLG1–4 subfamily of proteins, the CASK subfamily of proteins and MPP5 proteins play an important role in the organization of the presynaptic scaffold that forms the active zone regulating the trafficking of channels and receptors (Hsueh 2006; Thomas et al. 2010).

Although MAGUKs are best known for their function in the mature synapse, it has been established that they also participate in synapse formation. For instance, dlg mutants in Drosophila have morphological defects in their NMJ synaptic boutons (Budnik et al. 1996; Mendoza-Topaz et al. 2008). In mammals, this is not so clear, probably due to genetic redundancy, although overexpression of PSD95 and SAP97 can increase the size of spines and promote the formation of multi-innervated spines in hippocampal neurons (Poglia et al. 2011). Expression data have shown that among DLG-type MAGUK proteins, SAP102 is strongly expressed during prenatal and early postnatal life, indicating an important function during synapse formation. A recent study shows that SAP102 KO has a reduced number of thalamocortical projections innervating the somatosensory cortex (Crocker-Buque et al. 2016).

Adult synaptic function studies of PSD family members have been challenging due to partial redundancy between several PSD-type of proteins. In order to overcome the redundancy in functions of PSD95, PSD93, and SAP102, Chen et al. (2015) used a triple RNAi (mRNA interference) approach to knockdown the three proteins. Acute MAGUK knockdown decreases AMPA and NMDA receptor synaptic transmission in hippocampal synapses. Furthermore, a reduction in the size of the PSD and an increase in the number of silent synapses (devoid of receptors) is also observed. This reinforces the idea that MAGUK proteins anchor these receptor types in the PSD in the adult organism. MAGUKs also act as anchor proteins in the presynaptic site. In Drosophila, the absence of DLG in this region decreases action potential evoked release probability and disrupts the localization of the voltage-dependent calcium channel cacophony (Astorga et al. 2016).

MAGUKs in Epithelial Function

Epithelial cells form selective barriers in a variety of tissues. This specialization involves the compartmentalization of their cell membranes into apical and basolateral domains. Generation of this separation requires the presence of tight junctions between epithelial cells that limit diffusion between the two compartments. Several MAGUK proteins are abundant in tight junctions and play important roles in the control of epithelial polarity, adhesion, and cell proliferation (Funke et al. 2005). The main actors in these processes come from the ZO1, MPP5, and MAGI subfamilies.

In a typical epithelium, the apical side faces the lumen and the basolateral side communicates with the underlying tissue. The functional homologs of mammalian cell tight junctions in Drosophila are the septate junctions. Genetic studies in this organism have unveiled the role of two MAGUK proteins in the organization of these structures, DLG and Stardust. In Drosophila mutants of the MPP5 ortholog stardust, the epithelial junctions do not develop, resulting in embryonic lethality; furthermore DE-cadherin and Armadillo (two components of the cell adhesion complexes) do not localize properly (Grawe et al. 1996).

In turn in Drosophila epithelia, DLG organizes a basolateral complex that also contains Scribble (Scrib) and Lethal giant larvae, Lgl. It has been shown that in dlg mutants there is an increased size of proliferative epithelial tissue due to overproliferation of the cells, defects in the integrity of septate junction complexes, and apico-basal polarity (Woods et al. 1996). In mammals, DLG is also involved in epithelial organization, shown for instance in the lens (Rivera et al. 2009) and kidney epithelia (Naim et al. 2005). Another known function of DLG is as a tumor suppressor through its association with the tumor suppressor proteins adenomatous polyposis coli (APC) and phosphatase and tensin homolog (PTEN). DLG is also able to bind and suppress the transforming activity of viruses such as the human papillomavirus E6 (Roberts et al. 2012). Thus, MAGUK members participate in tissue integrity, cell polarity, and proliferation in epithelial tissue.

Summary

The MAGUK protein family is a highly conserved group of proteins that serve as scaffold proteins by combining the use of a handful of protein elements or functional modules that allow the generation of complexity at different subcellular and cellular levels. The participation of MAGUK proteins in the formation of the polarity in epithelia and subcellular domains such as the synapse is well studied and established. These studies have allowed for exploration of the role of MAGUKs in complex diseases such as schizophrenia, autism, and cancer (Elsum et al. 2012; Grant 2012; Hill et al. 2013; Fromer et al. 2014; Liu et al. 2014). More recent studies of the role of MAGUKs in other cell types or domains, such as immune cells (Humphries et al. 2012; Roche et al. 2013), cardiac cells (Gillet et al. 2015), the nodes of Ranvier (Zollinger et al. 2015), and the presynaptic active zone (Hsueh 2006; Astorga et al. 2016) and their role in processes beyond clustering and scaffolding, such as for example, vesicle trafficking (Walch 2013), will improve our understanding of the importance of this protein family and pave the way to their possible links to human diseases and hopefully aid with treatment of such diseases.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Cellular and Molecular Biology, Faculty of Biological SciencesPontificia Universidad Católica de ChileSantiagoChile
  2. 2.Department of Neuroscience and Biomedical Neuroscience Institute, Faculty of MedicineUniversidad de ChileSantiagoChile