8.A.24 The Ezrin/Radixin/Moesin-binding Phosphoprotein 50 (EBP50) Family

EBP50 is a Na+/H+ exchange regulatory cofactor, called NHE-RF or NHERF-1, of 358 aas (Slc9 isoform A3, regulatory factor 3). It is an adaptor protein that organizes a number of cell receptors and channels (Li et al., 2005). It contains two PDZ domains that bind to the cytoplasmic domains of a number of membrane channels, carriers and receptors to coordinate the assembly and trafficking of these transmembrane proteins. Most target proteins harboring a C-terminus recognition motif bind more-or-less equivalently to either of the PDZ domains, which contain identical core-binding motifs. However some substrates such as the type II sodium-dependent phosphate co-transporter (NPT2A), uniquely bind only one PDZ domain (Mamonova et al. 2015). 

NHERF1 (TC# 8.A.24.1.1 and NHERF2 (E3KARP) (TC# 8.A.24.1.2) are homologous adapter proteins that play roles in membrane protein targeting, trafficking, and sorting (Park et al. 2005). Both NHERF1 and 2 interact with the Na+/H+ exchanger, NHE3, through their C-terminally extended second PDZ domain. The last 30 amino acids of these PDZ domain proteins interact with ezrin (TC# 8.A.25.1.1). Both soluble NHERF proteins have been purified (Park et al. 2005).

The carboxyl terminus of NHERF interacts with the FERM domain (a domain shared by protein 4.1, ezrin, radixin, and moesin) of a family of actin-binding proteins called the ezrin-radixin-moesin family (TC #8.A.25). NHERF enhances the channel activities of cystic fibrosis transmembrane conductance regulator (CFTR) (TC #3.A.1.202.1). Binding of the FERM domain of ezrin to NHERF regulates the cooperative binding of NHERF to bring two cytoplasmic tails of CFTR into spatial proximity to each other. Ezrin binding activates the second PDZ domain of NHERF to interact with the cytoplasmic tails of CFTR (C-CFTR), so as to form a specific 2:1:1 (C-CFTR)2·NHERF·ezrin ternary complex. EPP50 is required both for plasma membrane localization and for maximal activation of CFTR (Broere et al., 2007). Without ezrin binding, the cytoplasmic tail of CFTR only interacts strongly with the first amino-terminal PDZ domain to form a 1:1 C-CFTR·NHERF complex. Because of the concentrated distribution of ezrin and NHERF in the apical membrane regions of epithelial cells and the diverse binding partners for the NHERF PDZ domains, the regulation of NHERF by ezrin may be employed as a general mechanism to assemble channels and receptors in the membrane cytoskeleton (Li et al., 2005).

The sodium-dependent glutamate transporter, glutamate transporter subtype 1 (GLT-1) is one of the main glutamate transporters in the brain. GLT-1 contains a COOH-terminal sequence similar to one in an isoform of Slo1 K+ channel protein previously shown to bind MAGI-1 (membrane-associated guanylate kinase with inverted orientation protein-1), a member of the EBP50 family (TC#8.A.24) (Zou et al., 2011). MAGI-1 is a scaffold protein which allows the formation of complexes between certain transmembrane proteins, actin-binding proteins, and other regulatory proteins. MAGI-1 is a binding partner of GLT-1. The interaction between MAGI-1 and GLT-1 was confirmed by co-immunoprecipitation. Immunofluorescence of MAGI-1 and GLT-1 demonstrated that the distribution of MAGI-1 and GLT-1 overlapped in astrocytes. Co-expression of MAGI-1 with GLT-1 in C6 Glioma cells resulted in a significant reduction in the surface expression of GLT-1, as assessed by cell-surface biotinylation. On the other hand, partial knockdown of endogenous MAGI-1 expression by small interfering RNA in differentiated cultured astrocytes increased glutamate uptake and the surface expression of endogenous GLT-1. Knockdown of MAGI-1 increased dihydrokainate-sensitive, Na+-dependent glutamate uptake, indicating that MAGI-1 regulates GLT-1-mediated glutamate uptake. These data suggest that MAGI-1 regulates surface expression of GLT-1 and the level of glutamate in the hippocampus (Zou et al., 2011). 

Many protein of TC families 8.A.22 and 8.A.24 and others contain PDZ, SH3 and kinase domains involved in signal transduction, often interacting with receptors and transporters. Therefore, these two families share about 400 aas in common.  PDZ proteins of the NHERF family act to stabilize and organize membrane targeting of multiple transmembrane proteins, including many clinically relevant drug transporters. These PDZ proteins are normally abundant at apical membranes, where they tether membrane-delimited transporters. NHERF expression is high at the apical membrane in polarized tissue such as intestinal, hepatic, and renal epithelia. NHERF proteins are determinants of drug transporter function in addition to their role in controlling membrane abundance and localization. They may have clinically significant roles in pharmacokinetics and pharmacodynamics of several pharmacologically active compounds and may affect drug action in cancer and chronic kidney disease. For these reasons, NHERF proteins represent a novel class of post-translational mediators of drug transport and novel targets for new drug development (Walsh et al. 2015).


 

References:

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Examples:

TC#NameOrganismal TypeExample
8.A.24.1.1

NHERF1; NHERF-1; EBP50; SlcA3R1.  Na+/H+ exchanger regulatory factor (NHERF) proteins are a family of PSD-95/Discs-large/ZO-1 (PDZ)-scaffolding proteins, three of which (NHERFs 1-3) are localized to the brush border in kidney and intestinal epithelial cells. All NHERF proteins are involved in anchoring membrane proteins that contain PDZ recognition motifs to form multiprotein signaling complexes.  These NHERF proteins exhibit differential mobility in membranes (Yang et al. 2013).  Sites involved in binding to NPT2A (TC# 2.A.58.1.1) have been identified (Mamonova et al. 2015).  Dynamic structures of the full-length NHERF1 influences signaling complex assembly (Bhattacharya et al. 2019). Thus, modulation of the intrinsic flexibility of NHERF1 by disease-associated point mutations alters assembly.

Animals

SLC9A3R1 of Homo sapiens

 
8.A.24.1.10

Golgi-associated PDZ and coiled-coil motif-containing protein, PIST or GOPC, of 462 aas and 1 possible N-terminal TMS.  The protein plays a role in intracellular protein trafficking and degradation, but also regulates CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels (Cheng et al. 2004; He et al. 2004). It also regulates the intracellular trafficking of the ADR1B receptor and plays a role in autophagy. Overexpression results in CFTR intracellular retention and degradation in the lysosomes (Cheng et al. 2002). The retention of Golgi membrane proteins can also be mediated by the Bre5p/Ubp3p deubiquitinase complex (Wang et al. 2020).

 

PIST of Homo sapiens

 
8.A.24.1.11

CASK ser/thr protein kinase of 898 aas and 0 probable TMSs; it activates Eag (1.A.1.20.6).

Animals

CASK of Drosophila melanogaster

 
8.A.24.1.12

Glutamate receptor-interacting protein 1, GRIP1, of 1128 aas and possibly one C-terminal TMS. It may play a role as a localized scaffold for the assembly of multiprotein signaling complexes and as a mediator of the trafficking of its binding partners at specific subcellular location in neurons (Brückner et al. 1999). Through complex formation with NSG1, GRIA2 and STX12, it controls the intracellular fate of AMPAR and the endosomal sorting of the GRIA2 subunit toward recycling and membrane targeting. It regulates the surface expression and synaptic stabilization of AMPARs by direct interaction with several members of the AMPAR family, and thereby  regulates synaptic plasticity in learning and memory (Tan et al. 2020).

GRIP1 of Homo sapiens

 
8.A.24.1.13

Tight Junction Protein ZO3, TJPZO3, of 919 aas and 1 moderatedly hudrophobic potential TMS near the N-terminus of the protein. Its function may overlap with that of TJPZ1 (TC# 8.A.24.1.9). With TJP2 and TJP3, it participates in the junctional retention and stability of the transcription factor DBPA. TJP1, TJP2, and TJP3 are closely related scaffolding proteins that link tight junction (TJ) transmembrane proteins such as claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton (Furuse et al. 1994, Fanning et al. 1998).

TJPZO3 of Homo sapiens

 
8.A.24.1.2

Solute carrier family 9, subfamily A (NHE3 cation proton antiporter 3 regulatory factor), member 3 regulator 2, SLC9A3R2, SNX27 (sorting nexin 27) or NHERF2 of 337 aas.  It binds erzin and affects dexamethasone stimulated NHE3 activity (Yang et al. 2015).  It also regulates several other transporters including CFTR (TC# 3.A.1.202.1) (Zhang et al. 2017). SNX27 directly interacts with DRA (SLC26A3; TC# 2.A.53.2.18) in early endosomes and mediates its direct recycling to facilitate high activity in lipid rafts in the apical plasma membrane (Bannert et al. 2020).

Animals

SLC9A3R2 of Homo sapiens

 
8.A.24.1.3

Na+/H+ exchange regulatory factor (NHERF) or discs large homologue 4, PSD-95, PSD95, Dig4, Digh4 of 724 aas and 0 TMSs. Acts to stabilize and organize membrane targeting of multiple transmembrane proteins, including many clinically relevant drug transporters. These PDZ proteins are normally abundant at apical membranes, where they tether membrane-delimited transporters. NHERF expression is particularly high at the apical membrane in polarized tissue such as intestinal, hepatic, and renal epithelial tissues (Walsh et al. 2015). DLG4 or PSD95 interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels and is required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. Moreover, DLG4 may reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. It also regulates the intracellular trafficking of ADR1B and controls AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density, keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression.  This involves palmitoylation (Jeyifous et al. 2016). Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes forms highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping (Zeng et al. 2019). AMPA receptor (AMPAR) trafficking in long-term potentiation (LTP) of excitatory synaptic transmission is well established. PSD-95 captures AMPARs via an interaction with the AMPAR auxiliary subunits-transmembrane AMPAR regulatory proteins (TARPs). The TARP/PSD-95 complex is an essential interaction underlying AMPAR trafficking and LTP (Ravi et al. 2022).

Animals

PSD95 of Homo sapiens

 
8.A.24.1.4

Group II metabotropic glutamate receptor, mGluR2/3, interacting protein, Grip2, of 1043 aas.  May play a role as a localized scaffold for the assembly of multiprotein signaling complexes and as mediator of the trafficking of its binding partners at specific subcellular locations in neurons. In mutant mice, the mGluR2/3 agonist, LY379268, restores excitatory and inhibitory defects with similar efficiency as olanzapine in a two-hit schizophrenia mouse model (Engel et al. 2016).

Grip2 of Rattus norvegicus (Rat)

 
8.A.24.1.5

Synaptojanin-2 binding protein, Omp25, of 145 aas with a C-terminal TMS (C-tail-anchored mitochondrial outer membrane protein) (Setoguchi et al. 2006).

Omp25 of Homo sapiens

 
8.A.24.1.6

MAGI-2 or MAGI2 of 1455 aas. Scaffold protein at synaptic junctions, assembling neurotransmitter receptors and cell adhesion proteins (Wu et al. 2000). It is a multi-PDZ domain scaffolding protein that interacts with several different ligands in brain, including hyperpolarization-activated cation channels, beta1-adrenergic receptors, and NMDA receptors.  MAGI-2 is a strong candidate for linking TARP/AMPA receptor complexes to a wide range of other postsynaptic proteins and pathways (Deng et al. 2006).

 

MAGI2 of Homo sapiens

 
8.A.24.1.7

Disc large homolog, 1DLG1 or SAP97, of 904 aas and 0 TMSs. Essential multidomain scaffolding protein required for normal development and lymphocyte activation (Xavier et al. 2004). Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. May play a role in adherens junction assembly, signal transduction, cell proliferation and synaptogenesis. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 and Kv1.5 channels (El-Haou et al. 2009).

DLG1 of Homo sapiens

 
8.A.24.1.8

Stardust, Sdt, of 879 aas and 1 N-terminal TMS.  Sdt is a scaffolding protein that stabilizes the transmembrane protein, Crumbs (TC# 9.B.87.1.11), a conserved regulator of apical-basal epithelial polarity (Das and Knust 2017).

Sdt of Drosophila melanogaster (Fruit fly)

 
8.A.24.1.9

Zonula occludens-1 (ZO-1) (tight junction protein, TJP1) of 1748 aas. Regulates intestinal barrier function (Nicolodi and Sicuteri 1996), gap and tight junctions (Giepmans 2006; Yun et al. 2017), the organic cation/carnitine transporter, OCTN2 (Jurkiewicz et al. 2017), and CFTR (Ruan et al. 2014) among others. It may have 4 C-terminal TMSs. Wine-processed Chuanxiong Rhizoma enhances efficacy of aumolertinib against EGFR mutant non-small cell lung cancer xenografts in nude mouse brain (Niu et al. 2023).

ZO-1 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.24.2.1

Syntenin-1, SDCBP, of 298 aas and 1 C-terminal TMS, is also called syndecan binding protein-1, scaffold protein Pbp1, and melanoma differentiation-associated protein 9 (MDA-9) (Mitsou et al. 2017). Multifunctional adapter protein involved in a diverse array of functions including trafficking of transmembrane proteins, neuro and immunomodulation, exosome biogenesis, and tumorigenesis (Philley et al. 2016). Syndecans can regulate stretch-activated ion channels. The structure and function of the syndecans have been reviewed (Mitsou et al. 2017). ESCRT-to-membrane coupling via ALIX/syntenin/syndecan-4 is required for completion of cytokinesis (Addi et al. 2020).

Syntenin-1 of Homo sapiens

 
8.A.24.2.2

Amyloid-beta A4 precursor protein-binding family A member 1, Mint1 or APBA1, of 837 aas and 3 or more C-terminal TMSs. Mint1 functions in synaptic vesicle exocytosis by binding to Munc18-1, an essential component of the synaptic vesicle exocytotic machinery. It may also modulate processing of the amyloid-beta precursor protein (APP) and hence formation of APP-beta.  Munc18 bridges the few syntaxin molecules residing on granules to the syntaxin cluster on the plasma membrane, suggesting that the number of syntaxins on vesicles determines docking and fusion probability (Borisovska 2018).

 

Mint1 of Homo sapiens

 
8.A.24.2.3

Amyloid-beta A4 precursor protein-binding family A member 2, APBA2 or Mint2, of 749 aas and 3 or more C-terminal TMSs. Mint1 and 2, of the X11 protein family, are multidomain proteins composed of a conserved PTB domain and two C-terminal PDZ domains. They are involved in formation of multiprotein complexes, and two of the family members, X11alpha and X11beta, are expressed primarily in neurons. Through interactions with other neuronal proteins, they may modulate processing of APP and accumulation of Abeta (Rogelj et al. 2006).

Mint2 of Homo sapiens

 
8.A.24.2.4

Brain nitric oxide synthase, NOS1, of 1434 aas and probably 0 TMSs. It produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. It probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR. Major depressive disorder (MDD) is one of the most common mental disorders. Sun et al. 2022 designed a fast-onset antidepressant that works by disrupting the interaction between the serotonin transporter (SERT; TC# 2.A.22.1.1) and neuronal nitric oxide synthase (nNOS) in the dorsal raphe nucleus (DRN). Chronic unpredictable mild stress (CMS) selectively increases the SERT-nNOS complex in the DRN in mice. Augmentation of SERT-nNOS interactions in the DRN causes a depression-like phenotype and accounts for CMS-induced depressive behaviors. Disrupting the SERT-nNOS interaction produces a fast-onset antidepressant effect by enhancing serotonin signaling in forebrain circuits. A small-molecule compound, ZZL-7 elicits an antidepressant effect 2 hours after treatment without undesirable side effects. This compound, or analogous reagents, may serve as a new, rapidly acting treatment for MDD (Sun et al. 2022).

NOS1 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
8.A.24.3.1

PRKCA-binding protein, PICK1, of 229 aas and possibly one TMS near the N-terminus. It is a probable adapter protein that binds to and organizes the subcellular localization of a variety of membrane proteins containing PDZ recognition sequences. It is involved in the clustering of various receptors, possibly by acting at the receptor internalization level. It plays a role in synaptic plasticity by regulating the trafficking and internalization of AMPA receptors and may be regulated upon PRKCA activation. It may regulate ASIC1/ASIC3 channels.

PICK1 of Homo sapiens