Sodium-hydrogen antiporter 3 regulator 1 explained

Sodium-hydrogen antiporter 3 regulator 1 is a regulator of Sodium-hydrogen antiporter 3. It is encoded by the gene SLC9A3R1. It is also known as ERM Binding Protein 50 (EBP50) or Na+/H+ Exchanger Regulatory Factor (NHERF1). It is believed^[1] to interact via long-range allostery, involving significant protein dynamics.

Mechanism

Members of the ezrin (VIL2; MIM 123900)-radixin (RDX; MIM 179410)-moesin (MSN; MIM 309845) (ERM) protein family are highly concentrated in the apical aspect of polarized epithelial cells. These cells are studded with microvilli containing bundles of actin filaments, which must attach to the membrane to assemble and maintain the microvilli. The ERM proteins, together with merlin, the NF2 (MIM 607379) gene product, are thought to be linkers between integral membrane and cytoskeletal proteins, and they bind directly to actin in vitro. Actin cytoskeleton reorganization requires the activation of a sodium/hydrogen exchanger (SLC9A3; MIM 182307). SLC9A3R1 is an ERM-binding protein.[supplied by OMIM]^[2]

Interactions

Sodium-hydrogen antiporter 3 regulator 1 has been shown to interact with:

• ADRB2,^{[3] [4] [5]}
• Beta-catenin,^[6]
• CFTR,^{[4] [7] [8] [9] [10] [11]}
• GNAQ,^[12]
• OPRK1,^{[13] [14]}
• PAG1,^[15]
• PDGFRA,
• PDGFRB,^[16]
• PDZK1,^[17]
• PTH1R,^[18]
• SLC4A8,^{[19] [20]}
• YAP1,^[21] and
• EZR^{[15] [22]}

See also

• Cystic fibrosis transmembrane conductance regulator
• Ezrin
• Moesin
• Neutron spin echo
• Radixin
• Solute carrier family

Further reading

• Weinman EJ, Steplock D, Wang Y, Shenolikar S . Characterization of a protein cofactor that mediates protein kinase A regulation of the renal brush border membrane Na(+)-H+ exchanger . J. Clin. Invest. . 95 . 5 . 2143–9 . 1995 . 7738182 . 10.1172/JCI117903 . 295815 .
• Yun CH, Oh S, Zizak M, etal . cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein . Proc. Natl. Acad. Sci. U.S.A. . 94 . 7 . 3010–5 . 1997 . 9096337 . 10.1073/pnas.94.7.3010 . 20313 . 1997PNAS...94.3010Y . free .
• Murthy A, Gonzalez-Agosti C, Cordero E, etal . NHE-RF, a regulatory cofactor for Na(+)-H+ exchange, is a common interactor for merlin and ERM (MERM) proteins . J. Biol. Chem. . 273 . 3 . 1273–6 . 1998 . 9430655 . 10.1074/jbc.273.3.1273 . free .
• Hall RA, Spurney RF, Premont RT, etal . G protein-coupled receptor kinase 6A phosphorylates the Na(+)/H(+) exchanger regulatory factor via a PDZ domain-mediated interaction . J. Biol. Chem. . 274 . 34 . 24328–34 . 1999 . 10446210 . 10.1074/jbc.274.34.24328 . free .
• Cao TT, Deacon HW, Reczek D, etal . A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor . Nature . 401 . 6750 . 286–90 . 1999 . 10499588 . 10.1038/45816 . 1999Natur.401..286C . 4386883 .
• Breton S, Wiederhold T, Marshansky V, etal . The B1 subunit of the H+ATPase is a PDZ domain-binding protein. Colocalization with NHE-RF in renal B-intercalated cells . J. Biol. Chem. . 275 . 24 . 18219–24 . 2000 . 10748165 . 10.1074/jbc.M909857199 . free .
• Tang Y, Tang J, Chen Z, etal . Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF . J. Biol. Chem. . 275 . 48 . 37559–64 . 2001 . 10980202 . 10.1074/jbc.M006635200 . free .
• Gisler SM, Stagljar I, Traebert M, etal . Interaction of the type IIa Na/Pi cotransporter with PDZ proteins . J. Biol. Chem. . 276 . 12 . 9206–13 . 2001 . 11099500 . 10.1074/jbc.M008745200 . cotransporter . free .
• Reczek D, Bretscher A . Identification of Epi64, a Tbc/Rabgap Domain–Containing Microvillar Protein That Binds to the First PDZ Domain of Ebp50 and E3karp . J. Cell Biol. . 153 . 1 . 191–206 . 2001 . 11285285 . 10.1083/jcb.153.1.191 . 2185518 .
• Karthikeyan S, Leung T, Ladias JA . Structural basis of the Na+/H+ exchanger regulatory factor PDZ1 interaction with the carboxyl-terminal region of the cystic fibrosis transmembrane conductance regulator . J. Biol. Chem. . 276 . 23 . 19683–6 . 2001 . 11304524 . 10.1074/jbc.C100154200 . free .
• Karthikeyan S, Leung T, Birrane G, etal . Crystal structure of the PDZ1 domain of human Na(+)/H(+) exchanger regulatory factor provides insights into the mechanism of carboxyl-terminal leucine recognition by class I PDZ domains . J. Mol. Biol. . 308 . 5 . 963–73 . 2001 . 11352585 . 10.1006/jmbi.2001.4634 .

Notes and References

1. Farago B, Li J, Cornilescu G, Callaway DJ, Bu Z . Activation of nanoscale allosteric protein domain motion revealed by neutron spin echo spectroscopy . Biophys. J. . 99 . 10 . 3473–82 . November 2010 . 21081097 . 2980739 . 10.1016/j.bpj.2010.09.058 . 2010BpJ....99.3473F.
2. Web site: Entrez Gene: SLC9A3R1 solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 1.
3. May 2002 . Karthikeyan S, Leung T, Ladias JA . Structural determinants of the Na+/H+ exchanger regulatory factor interaction with the beta 2 adrenergic and platelet-derived growth factor receptors . J. Biol. Chem. . 277 . 21 . 18973–8 . 11882663 . 10.1074/jbc.M201507200. free .
4. July 1998 . Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ . A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins . Proc. Natl. Acad. Sci. U.S.A. . 95 . 15 . 8496–501 . 9671706 . 21104 . 10.1073/pnas.95.15.8496. 1998PNAS...95.8496H . free .
5. April 1998 . Hall RA, Premont RT, Chow CW, Blitzer JT, Pitcher JA, Claing A, Stoffel RH, Barak LS, Shenolikar S, Weinman EJ, Grinstein S, Lefkowitz RJ . The beta2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange . Nature . 392 . 6676 . 626–30 . 9560162 . 10.1038/33458. 1998Natur.392..626H . 4422540 .
6. July 2003 . Shibata T, Chuma M, Kokubu A, Sakamoto M, Hirohashi S . EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma . Hepatology . 38 . 1 . 178–86 . 12830000 . 10.1053/jhep.2003.50270. 10325091 . free .
7. March 2003 . Hegedüs T, Sessler T, Scott R, Thelin W, Bakos E, Váradi A, Szabó K, Homolya L, Milgram SL, Sarkadi B . C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins . Biochem. Biophys. Res. Commun. . 302 . 3 . 454–61 . 12615054 . 10.1016/S0006-291X(03)00196-7.
8. May 1998 . Wang S, Raab RW, Schatz PJ, Guggino WB, Li M . Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR) . FEBS Lett. . 427 . 1 . 103–8 . 9613608 . 10.1016/S0014-5793(98)00402-5. 20803242 . free .
9. September 2000 . Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, Pfeiffer J, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, Stanton BA . The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane . J. Biol. Chem. . 275 . 35 . 27069–74 . 10852925 . 10.1074/jbc.M004951200. free .
10. February 2003 . Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR . The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins . J. Biol. Chem. . 278 . 8 . 6440–9 . 12471024 . 10.1074/jbc.M211050200. free .
11. July 1998 . Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL . An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton . J. Biol. Chem. . 273 . 31 . 19797–801 . 9677412 . 10.1074/jbc.273.31.19797. free .
12. October 2002 . Rochdi MD, Watier V, La Madeleine C, Nakata H, Kozasa T, Parent JL . Regulation of GTP-binding protein alpha q (Galpha q) signaling by the ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) . J. Biol. Chem. . 277 . 43 . 40751–9 . 12193606 . 10.1074/jbc.M207910200. free .
13. June 2004 . Huang P, Steplock D, Weinman EJ, Hall RA, Ding Z, Li J, Wang Y, Liu-Chen LY . kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins . J. Biol. Chem. . 279 . 24 . 25002–9 . 15070904 . 10.1074/jbc.M313366200. free .
14. July 2002 . Li JG, Chen C, Liu-Chen LY . Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate . J. Biol. Chem. . 277 . 30 . 27545–52 . 12004055 . 10.1074/jbc.M200058200. free .
15. October 2001 . Brdicková N, Brdicka T, Andera L, Spicka J, Angelisová P, Milgram SL, Horejsí V . Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton . FEBS Lett. . 507 . 2 . 133–6 . 11684085 . 10.1016/S0014-5793(01)02955-6. 12676563 . free .
16. November 2000 . Maudsley S, Zamah AM, Rahman N, Blitzer JT, Luttrell LM, Lefkowitz RJ, Hall RA . Platelet-derived growth factor receptor association with Na(+)/H(+) exchanger regulatory factor potentiates receptor activity . Mol. Cell. Biol. . 20 . 22 . 8352–63 . 11046132 . 102142 . 10.1128/MCB.20.22.8352-8363.2000.
17. November 2003 . Gisler SM, Pribanic S, Bacic D, Forrer P, Gantenbein A, Sabourin LA, Tsuji A, Zhao ZS, Manser E, Biber J, Murer H . PDZK1: I. a major scaffolder in brush borders of proximal tubular cells . Kidney Int. . 64 . 5 . 1733–45 . 14531806 . 10.1046/j.1523-1755.2003.00266.x. free .
18. June 2002 . Mahon MJ, Donowitz M, Yun CC, Segre GV . Na(+)/H(+) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling . Nature . 417 . 6891 . 858–61 . 12075354 . 10.1038/nature00816. 2002Natur.417..858M . 4379134 .
19. Dec 2002 . Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I . The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3 . J. Biol. Chem. . 277 . 52 . 50503–9 . 12403779 . 10.1074/jbc.M201862200. free .
20. March 2003 . Pushkin A, Abuladze N, Newman D, Muronets V, Sassani P, Tatishchev S, Kurtz I . The COOH termini of NBC3 and the 56-kDa H+-ATPase subunit are PDZ motifs involved in their interaction . Am. J. Physiol., Cell Physiol. . 284 . 3 . C667–73 . 12444018 . 10.1152/ajpcell.00225.2002. 7070088 .
21. November 1999 . Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, Milgram SL . Yes-associated protein 65 localizes p62(c-Yes) to the apical compartment of airway epithelia by association with EBP50 . J. Cell Biol. . 147 . 4 . 879–90 . 10562288 . 2156157 . 10.1083/jcb.147.4.879.
22. October 1997 . Reczek D, Berryman M, Bretscher A . Identification of EBP50: A PDZ-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family . J. Cell Biol. . 139 . 1 . 169–79 . 9314537 . 2139813 . 10.1083/jcb.139.1.169.