It’s Maguk

Ever hear of membrane-associated guanylate kinases?  I’ll let one team of researchers describe them:

Membrane-associated guanylate kinases (MAGUKs) form a family of scaffolding proteins, engaged in the organisation of multiprotein complexes, which are often associated with cellular junctions or signalling complexes, such as the vertebrate tight junction (TJ) or the Drosophila septate junction (SJ) in epithelial cells or the neuromuscular junction (NMJ). Their capacity to serve as a platform for recruiting larger protein assemblies results from the presence of several protein-protein interaction domains: one to three PDZ (PSD-95/Discs large/zonula occludens (ZO)-1)-domains, an SH3-(Src homology-3)-domain and a guanylate kinase (GUK)-domain. Some members additionally contain one or two L27 (Lin-2/Lin-7)-domains in their N-terminus.. This modular structure is ideally suited to recruit a variety of components into a protein complex, the composition of which often depends on the cell type and/or developmental stage. In addition, MAGUK-encoding genes often give rise to more than one isoform by alternative splicing, thus increasing the possibility of multiple interactions, localisations and/or functions. [1]

So we have a modular scaffold protein that associates with protein complexes involved in connecting cells together.  It is “ideally suited to recruit a variety of components into a protein complex” and its structure is poised to be exploited by alternative splicing. The MAGUKs play important regulatory roles in this multicellular context, “where they coordinate multiple binding partners, including cell adhesion molecules and ion channels.” [2]   The MAGUKs thus link these interactions to downstream signaling events.  Not surprisingly, they play an important role in brain function:

In the postsynaptic density of excitatory glutamatergic synapses, membrane associated guanylate kinase (MAGUK) proteins, such as Post-Synaptic Density 95 (PSD-95), organize ionotropic glutamate receptors and their associated signalling proteins regulating the strength of synaptic activity. Modifications of MAGUK proteins function in the glutamatergic synapse such as alterations of MAGUK proteins interaction with N-Methyl-D-Aspartate (NMDA) receptors regulatory subunits are common events in several neurodegenerative disorders. Thus, a better knowledge and understanding of MAGUK structure and function as well as of the molecular events regulating MAGUK-mediated interactions in the glutamatergic synapse could lead to the identification of new targets for pharmaceutical intervention for neurodegenerative diseases. [3]

It would seem that the MAGUKs would be a very useful component of any genomic toolkit that was front-loaded to facilitate the emergence of metazoan life.  So when did these MAGUKs originate?

According to one study from 2007 [4], MAGUK was a metazoan innovation:

To elucidate the origin and the evolutionary history of the MAGUK family, we investigated full-length cDNA, EST and genomic sequences of species in major phyla. These data indicated that MAGUKs are present only in metazoan species and not encoded in protozoans, bacteria or plants.


We attempted to identify MAGUK proteins and closely related structural homologs, which are vital for metazoan processes such as cell to cell communication, in these species as well, however, none could be found in protozoans. In addition, MAGUK sequences were not found in the genomes of bacteria, fungi and plant species. This suggests that the formation of the MAGUK structure, with its characteristic and centrally-positioned, non-functioning GK domain is essentially of metazoan origin and we speculate that the MAGUKs initially played important roles in cell to cell communication.

That study make bunny sad.

Don’t cry bunnah.  Look what another research team just discovered [5]:

These MAGUK proteins were believed to be exclusive to Metazoa. However, a MAGUK gene was recently identified in an EST survey of Capsaspora owczarzaki, an unicellular organism that branches off near the metazoan clade. To further investigate the evolutionary history of MAGUK, we have undertook a broader search for this gene family using available genomic sequences of different opisthokont taxa.


In this study we have identified several MAGUK and MAGUK-like homologs in premetazoan taxa. Overall, our data show that the MAGUK protein gene family is not exclusive to Metazoa. This gene family most probably diversified within the opisthokonts before the divergence between Capsaspora and the Choanoflagellata + Metazoa clade. Thus, DLG, MPP and MAGI were already present in the last common ancestor of the Metazoa, choanoflagellates and Capsaspora+Ministeria (Filasterea) clade. The family further diversified within metazoans, most probably in two major episodes (early metazoan and early vertebrate evolution) and up to ten different MAGUK types evolved with different roles.

So MAGUKs were alive and well in unicellular organisms that predated the emergence of metazoans.  Notice also that the two periods of expansion correlate with the emergence of metazoa, then vertebrates.

And lets not forget that proteins that actually connect cells together at vertebrate tight junctions and synapses also existed before metazoans [6]:

Cadherin-mediated cell adhesion and signaling is essential for metazoan development and yet is absent from all other multicellular organisms. We found cadherin genes at numbers similar to those observed in complex metazoans in one of the closest single-celled relatives of metazoans, the choanoflagellate Monosiga brevicollis. Because the evolution of metazoans from a single-celled ancestor required novel cell adhesion and signaling mechanisms, the discovery of diverse cadherins in choanoflagellates suggests that cadherins may have contributed to metazoan origins.


The evolution of animals (metazoans) from their unicellular ancestors required the emergence of novel mechanisms for cell adhesion and cell-cell communication. One of the most important cell adhesion mechanisms for metazoan development is integrin-mediated adhesion and signaling. The integrin adhesion complex mediates critical interactions between cells and the extracellular matrix, modulating several aspects of cell physiology. To date this machinery has been considered strictly metazoan specific. Here we report the results of a comparative genomic analysis of the integrin adhesion machinery, using genomic data from several unicellular relatives of Metazoa and Fungi. Unexpectedly, we found that core components of the integrin adhesion complex are encoded in the genome of the apusozoan protist Amastigomonas sp., and therefore their origins predate the divergence of Opisthokonta, the clade that includes metazoans and fungi. [7]

So the rivets and staples that are used to connect your stomach and brain cells together, for example, existed before sponges and jellyfish came into existence.  They existed in a unicellular state.  And the components that link these rivets and staples to the signaling circuits inside your brain and stomach cells likewise existed before sponges and jellyfish came into existence. As we survey more and more genomes, we’re finding more and more of the metazoan toolkit to exist in unicellular organisms.  It’s almost as if the origin of metazoa was in the cards.


1. Bachmann A, Draga M, Grawe F, Knust E. 2008. On the role of the MAGUK proteins encoded by Drosophila varicose during embryonic and postembryonic development.  BMC Dev Biol. 8:55.

2.  Thomas U, Kobler O, Gundelfinger ED. 2010. The Drosophila larval neuromuscular junction as a model for scaffold complexes at glutamatergic synapses: benefits and limitations.  J Neurogenet. 24(3):109-19.

3. Gardoni F. 2008.  MAGUK proteins: new targets for pharmacological intervention in the glutamatergic synapse. Eur J Pharmacol. 585(1):147-52.

4. te Velthuis AJ, Admiraal JF, Bagowski CP. 2007. Molecular evolution of the MAGUK family in metazoan genomes. BMC Evol Biol. 7:129.

5. de Mendoza A, Suga H, Ruiz-Trillo I. 2010. Evolution of the MAGUK protein gene family in premetazoan lineages. BMC Evol Biol. 10:93.

6. Abedin M, King N.  2008. The premetazoan ancestry of cadherins.  Science 319(5865):946-8.

7. Sebé-Pedrós A, Roger AJ, Lang FB, King N, Ruiz-Trillo I. 2010. Ancient origin of the integrin-mediated adhesion and signaling machinery.  Proc Natl Acad Sci U S A. 107(22):10142-7.


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