LIG_DLG_GKlike_1

Post-synaptic densities (PSDs) are densely packed multi-protein structures orchestrating synaptic formation and function at the distal tip of dendritic spine heads (Carlin,1980 Chen,2008 Sheng,2011) that are enriched in neurotransmitter receptors, adhesion molecules, scaffold proteins, signalling enzymes, and cytoskeletal components. The spatial and temporal organization of scaffold protein-mediated protein complexes at the core of the PSD is pivotal for synaptic signalling and plasticity as those serve as bridges linking the upstream glutamate receptors (NMDA-type and AMPA-type glutamate receptors) with the downstream signalling complexes and the cytoskeleton (Won,2017 Zhu,2016). The PSD-95 family (also called discs large homologue, DLG family) of membrane-associated guanylate kinases (MAGUKs), including PSD-95, PSD-93, SAP102, and SAP97, are the most abundant scaffold proteins in PSDs. PSD-95 directly binds to Synapse-associated protein 90 (SAP90)/PSD-95-associated proteins (SAPAPs, also known as DLGAPs or GKAPs), which in turn bind to the Shank family proteins, forming the PSD-95/SAPAP/Shank core complex of PSD (Kim,1997 Naisbitt,1999). This core complex is thought to be critical for synaptic development and transmission. Loss of any of its components results in the loss of AMPAR-containing synapses and weaker synaptic transmissions (Zhu,2017).
MAGUKs contain a Guanylate kinase-like (GK-like) domain (InterPro: IPR008144) that diverged from guanylate kinase enzymes (which catalyze phosphoryl transfer from ATP to GMP) near the appearance of animals in the evolutionary record. These diverged MAGUK GK-like domains of animals have lost catalytic activity but gained the ability to bind phosphorylated segments of proteins (Johnston,2012), as the GMP-binding site of GK has evolved into a specific pSer/pThr-binding pocket (Zhu,2011).
The interaction between the DLG family members and phosphorylated SAPAP proteins represents an essential link in the formation of the PSD-95/SAPAP/Shank postsynaptic core complex. SAPAPs bind the guanylate kinase (GK) domains of the PSD-95 family proteins (Kim,1997 Takeuchi,1997 Zhu,2017 Zhu,2011) and MAGI2 (Hirao,1998) through very strictly conserved short repeats, referred to as GK-binding repeats (GBRs). GBRs were considered to match a R..(S)Y[LMVI][RK]A motif, with the serine residue required to be phosphorylated for binding. Studies also established that non-PSD-specific MAGUK proteins, for instance the zona occludens protein ZO-1, the peripheral plasma membrane protein CASK and the regulator of neutrophil polarity MPP1 do not specifically bind the SAPAP motif even though they also possess GK-like domains (Takeuchi,1997). Wide conservation of this interaction motif is underlined by the fact that the D. melanogaster homologue of mammalian MAGUKs, Dlg1 could also bind the rat SAPAP GBRs with similar affinity as mammalian PSD-95 family proteins (Takeuchi,1997).
Some other proteins also employ similar phosphorylated motifs to bind the GK-like domain, although they usually bind somewhat weaker than SAPAPs. These include members of diverse protein families, like the synaptic scaffold protein BEGAIN (Deguchi,1998), the Rap‐specific GTPase‐activating protein SPAR, the mitotic spindle regulatory protein LGN (Zhu,2011) and Lgl, a component of the evolutionarily conserved Scribble complex (Zhu,2014).
Interestingly, while in these interactions the peptide pSer could not be changed to glutamic/aspartic acid without losing/largely weakening the interaction (Zhu,2017 Zhu,2011), in one known case of MAP1A the complex revealed a unique target recognition mode, where an aspartic acid of MAP1A (D2117) could mimic phospho-serine and bind to the 'phospho-site' of the PSD-95 GK (Xia,2017).