MAGUKs

MAGUKs, or membrane-associated guanylate kinase homologs, are a family of scaffold proteins that organize signaling complexes at cellular membranes. They are named for their guanylate kinase–like (GUK) domain, which in many members is catalytically inactive and serves as a protein-binding module rather than an enzyme. MAGUKs function primarily as adapters that link transmembrane receptors and channels to the cytoskeleton and to intracellular signaling pathways, thereby shaping membrane signaling domains.

Most MAGUKs share a modular architecture that includes PDZ domains (often multiple), an SH3 domain, and a GUK domain. Many also possess an N-terminal L27 domain that mediates assembly of protein complexes. Some members of the family, such as those in the ZO and DLG subfamilies, play additional roles in specialized junctions and polarity. Notable examples include the DLG (discs large) subfamily in vertebrates, which comprises DLG1 (SAP97), DLG2 (PSD-93), DLG3 (SAP102), and DLG4 (PSD-95); and the ZO (zonula occludens) subfamily, including ZO-1, ZO-2, and ZO-3, which organize tight junctions in epithelia and endothelia.

In the nervous system, MAGUKs are prominent at postsynaptic densities where they cluster and stabilize glutamate receptors (notably NMDA and AMPA receptors) and several signaling proteins, thereby influencing synaptic localization, maturation, and plasticity. In epithelia and other tissues, MAGUKs contribute to cell polarity and junctional integrity by coordinating interactions among receptors, adhesion molecules, and the cytoskeleton.

Dysregulation or mutations of MAGUKs have been linked to various neurological and developmental disorders, including autism spectrum disorders and epilepsy, reflecting their central role in organizing synaptic and membrane signaling networks.