PSD-95 (postsynaptic density protein 95) also known asSAP-90 (synapse-associated protein 90) is aprotein that in humans is encoded by theDLG4 (discs large homolog 4)gene.[5][6][7]
PSD-95 is a member of themembrane-associated guanylate kinase (MAGUK) family. WithPSD-93 it is recruited into the sameNMDA receptor andpotassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for theclustering of receptors, ion channels, and associated signaling proteins.[5] PSD-95 is the best studied member of the MAGUK-family ofPDZ domain-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, anSH3 domain, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density ofneurons,[8] and is involved in anchoring synaptic proteins. Its direct and indirect binding partners includeneuroligin,NMDA receptors,AMPA receptors, andpotassium channels.[9] It plays an important role insynaptic plasticity and the stabilization of synaptic changes duringlong-term potentiation.[10]
PSD-95 (encoded by DLG4) is a member of the MAGUK superfamily, and part of a subfamily which also includesPSD-93,SAP97 andSAP102. The MAGUKs are defined by their inclusion ofPDZ,SH3 andGUK domains, although many of them also contain regions homologous ofCaMKII,WW andL27 domains.[11] The GUK domain that they have is structurally very similar to that of theguanylate kinases, however it is known to be catalytically inactive as the P-Loop which bindsATP is absent. It is thought that the MAGUKs have subfunctionalized the GUK domain for their own purposes, primarily based on its ability to form protein-protein interactions with cytoskeleton proteins, microtubule/actin based machinery and molecules involved in signal transduction.
ThePDZ domain which are contained in the MAGUKs in varying numbers, is replicated three times over in PSD-95. PDZ domains are short peptide binding sequences commonly found at theC-terminus of interacting proteins. The three copies within the gene have different binding partners, due to amino acid substitutions within the PSD-95 protein and its ligands. The SH3 domain is again a protein-protein interaction domain. Its family generally bind to PXXP sites, but in MAGUKs it is known to bind to other sites as well. One of the most well known features is that it can form an intramolecular bond with the GUK domain, creating what is known as a GUK-SH3 'closed' state. The regulatory mechanisms and function are unknown but it is hypothesized that it may involve a hook region and acalmodulin binding region located elsewhere in the gene.
^Stathakis DG, Hoover KB, You Z, Bryant PJ (Nov 1997). "Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues".Genomics.44 (1):71–82.doi:10.1006/geno.1997.4848.PMID9286702.
^abSans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S, Wenthold RJ (June 2003). "NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex".Nat. Cell Biol.5 (6):520–30.doi:10.1038/ncb990.PMID12738960.S2CID13444388.
^abHou XY, Zhang GY, Yan JZ, Chen M, Liu Y (November 2002). "Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia".Brain Res.955 (1–2):123–32.doi:10.1016/S0006-8993(02)03376-0.PMID12419528.S2CID85751.
^abcIrie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K, Takai Y, Rosahl TW, Südhof TC (September 1997). "Binding of neuroligins to PSD-95".Science.277 (5331):1511–5.doi:10.1126/science.277.5331.1511.PMID9278515.
^abcInanobe A, Fujita A, Ito M, Tomoike H, Inageda K, Kurachi Y (June 2002). "Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses".Am. J. Physiol., Cell Physiol.282 (6): C1396–403.doi:10.1152/ajpcell.00615.2001.PMID11997254.
^Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (September 1995). "Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95".Science.269 (5231):1737–40.Bibcode:1995Sci...269.1737K.doi:10.1126/science.7569905.PMID7569905.
^Kim E, Sheng M (1996). "Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases".Neuropharmacology.35 (7):993–1000.doi:10.1016/0028-3908(96)00093-7.PMID8938729.S2CID23755452.
