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Function
PSD-95 is a scaffolding protein that is found in the postsynaptic density (PSD) in the excitatory neurons of the cerebral cortex. This protein belongs to the Membrane-associated guanylate kinases (MAGUK) family. The proteins of the MAGUK family have been found to be a key factor in many processes. These processes include the development of tissues, communications between cells, cellular charge activation, and signal transduction between cells just to name a few. [3] PSD-95 permeates the PSD, a large curved protein complex that lines the postsynaptic membrane (PSM) or the cellular interior of a synapse. This protein complex’s primary function is one of support. It is known to hold not only synaptic receptors in place in the membrane but it holds their respective signaling molecules as well. PSD-95 is integral to the organization of these receptors, as well as the downstream signaling proteins. Due to the scaffolding directive of PSD-95, its structure is actually a series of proteins to make a much larger binding protein complex. PSD-95 not only enriches synaptic transmissions but it is also known to play a major role in synaptic plasticity through the lattice it makes at the synaptic membrane.
With PSD-95 being so close to the cell membrane, it can be identified and labeled by antibodies from both sides of the plasma membrane. Due to its location it is able to interact with membrane bound proteins including ion channels, adhesion molecules, and various receptors. The most important of these interactions is considered to be its ability to sort signaling complexes in the plasma membrane.
Disease
There are more than 130 diseases are attributed to changes in the proteome of excitatory synapses. Given that PSD-95 belongs to the proteome of excitatory synapses, research has found that any mutations with PSD-95 caused complications not only for how quickly synapses transmitted neurotransmitters but its capability to conform to new stresses. Therefore, since PSD-95 is integral for synaptic stability, a decrease in PSD-95 has substantial neurological effects based on age and the area of the brain affected.
1.Media Prefrontal Cortex - Under normal circumstances, PSD-95 continues to increase from birth until peaking during adolescents. However, if the PSD-95 is decreased, it will affect the medial prefrontal cortex (mPFC) which is responsible for cognition, working memory, and sociability (Coley, 2019). Researchers found that the PSD-95 knockout mice lacked sociability and exhibited both learning and working memory deficiencies. The dysfunction of PSD-95 is believed to manifest to some degree in humans as either schizophrenia or as autism [4]. It has also been linked to Alzheimer’s by a research study.
2.Superior Temporal Sulcus - This research study focused on the superior temporal sulcus. The disease is mainly characterized by neuronal damage, neuronal death, and brain atrophy. The study found that in a group of post-mortem subjects; demented subjects had 50% less PSD-95 concentration than the control group. [5] This was compared to a group that had many of the same morphological signs as those with Alzheimer’s but suffered no adverse effects from it. This group had significantly more PSD-95 than a normal brain, perhaps to counter act the degrading aspects.
3.Corpus Striatum – A study of cocaine abuse using a mice study suggests that psychostimulants decrease the PSD-95 levels in both the dorsal and ventral portions of the striatum though the hippocampus and cortex were unaffected. While less than 2 injections made little change in PSD-95 levels, 3 to 10 injections resulted in substantial chronic PSD-95 loss; however, 11 or more injections showed no additional decreases. [6] When studied months after the last injection, the deficits in PSD-95 remained, suggesting long-term neuronal effects of drug use.
Structure
“The PSD-95 family of PDZ scaffold proteins is encoded by four genes (PSD-95/SAP90 (synapse-associated protein 90), PSD-93/chapsyn-110, SAP102 and SAP97). These proteins are characterized by three PDZ domains, an SRC homology 3 (SH3) domain, and a Guanylate Kinase-like (GK) domain." [7] PSD-95 is comprised of three PDZ domains, an SRC Homology3 (SH3), and a guanylate kinase-like (GK) domain. [8]
PDZ Domain: PDZ is a protein-interaction domain that can form large molecular structures by binding to other scaffolding proteins. The determining factor for a PDZ depends on the amino acid sequence of its ligands on their C terminal. The first two PDZ proteins in PSD-95 are arranged in a way such that they both have their C terminals capable of binding to their ligand from the same direction as the other. The and domains that bind to the NMDA receptor (NMDAR), NR2 subunits, and Kv1 channels are positioned in similar orientations. The third PDZ domain has its strongest interactions done by its C-terminal. Currently it is thought that an unbound domain is waiting to interact with its C-terminal protein.
Src-Homolgy 3 (SH3): The SH3 or shank subunit is a small portion of PSD-95. This roughly 60 amino acid long molecule is an extremely common subunit that is found in almost all cells. In PSD-95 the subunit exists near the end, farthest away from the cell membrane. Here this subunit can bind to a multitude of proteins; the most common proteins that it binds in this position are the horizontal proteins GKAP and SAPAP. This subunit is also made of domains, one of which is capable of polymerizing itself form its regular round shape into one that is more reminiscent of a sheet.
The combined SH3-GK structure of PSD-95 is characterized by an atypical hinge connecting the two. This compact fold allows regulatory proteins to bind at the hinge to switch from an intramolecular to intermolecular assembly. This switch could mediate PSD-95 oligomerization. [9]
Guanylate Kinase (GK): Normally or GK acts to phosphorylate Guanine Diphosphate (GDP) by taking a phosphate from a Guanine Monophosphate (GMP); however, in the case of it acting as domain for PSD-95, it has a much different function. While a part of PSD-95, acts as an anchor point. This can be seen when it assists with the organization of the spindles that form during mitosis. It has also been observed to assist in the process of cell adhesion.
FILAMENTS: In examining the PSD, an abundant number of filaments were discovered and categorized by dimension, shape, and their location on the PSD. A large number of filaments near the core are both straight and perpendicular to the PSD with dimensions of 5nm in diameter and 20nm long (Chen, 2008). Most of the vertical filaments were categorized as PSD-95, within the MAGUK family dimensions of 4nm in diameter and 20 nm long, and with their N terminal towards the post synaptic membrane (Chen, 2008).
Glutamate receptors, NMDA and APMA, are two known horizontal filaments, forming a large interconnected structure using PSD-95. These horizontal structures intersect with each other while also intertwining throughout the vertical filaments. The structure formed from the interaction of these proteins is known as the PSD.
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR): AMPAR is a horizontal filament that makes up the PSD inter-protein lattice. It was found that on average there are between 30 and 100 AMPAR proteins present in a PSD with a diameter of 400 nm and spaced approximately 24 nm apart. It was widely believed that a direct binding to the PSD existed between PSD-95 and AMPAR. However, research has discovered that although the AMPAR structures are an integral part of the PSD, a direct binding to PSD-95 has not been demonstrated; therefore, research is focusing on bridging molecules which binds to both AMPAR and PSD-95. Further study showed that Stargzin, a member of the TARP family of proteins, strongly binds to AMPAR and PSD-95, making it capable as the potential bridge.[10] As the AMPAR protein lines the outer edges of the PSD, it is reasonable to think that the radius of the PSD will influence the concentration of the AMPAR. This AMPAR protein binds to the center of one vertical filament with spacing of 20 nm. Similar to the NMDAR, the extracellular AMPAR is bound by a thin but long filament.
N-methyl-d-aspartate (NMDAR): NMDAR is a second horizontal filament that assists with the structure of the PSD. While one of the most important proteins of the PSD, it is only found near the center with spacing of 30nm. The NMDAR protein makes a rhombic-like framework that provides space for 16-25 receptors in the center. It is the largest protein of all of those in the PSD at a diameter of roughly 130 nm. It is found both within the cytoplasmic side of the membrane and the extracellular side. In both cases, it interacts with two vertical filaments found at each end of the protein. While the intracellular form is met with PSD-95 filaments, the extracellular form is met with very thin and delicate filaments within the synaptic cleft.
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