Gephyrin/GPHN: Proteins and Enzymes

Gephyrin (GPHN) is a core scaffolding protein found in the postsynaptic density (PSD) of inhibitory synapses. It is primarily localized to GABAergic and glycinergic synapses in the brain and is thought to be important for organizing the inhibitory PSD. GPHN has been shown to bind to multiple proteins in inhibitory PSDs including GABA-A receptors, glycine receptors, Neuroligin 2/NLGN2, Tubulin, Collybistin/ARHGEF9, GABARAP, Pin1, PtdIns3P, RAFT1, and VASP.

While the importance of many of these protein-protein interactions is still unknown, it is thought that GPHN is essential for the clustering of GABA-A and glycine receptors, inhibitory synaptic transmission, and long-term potentiation (LTP). GPHN is also expressed in non-neuronal tissue including skeletal muscle, heart, and liver, where it plays a role in the biosynthesis of a molybdenum cofactor.

Human GPHN is 736 amino acids (aa) in length with a predicted molecular weight of approximately 93 kDa. It is composed of three major domains: a 181 aa N-terminal G domain that possesses MPT Mo-transferase activity (aa 14-166), a 420 aa C-terminal E domain (aa 319-738) that contains an MPT adenyltransferase domain with an embedded homodimerization motif, and a 151 aa internal C domain (aa 167-318) that links the G and E domains and contains many post-translational modification and protein binding sites. Over aa 2-188, human and mouse Gephyrin are identical in amino acid sequence.