Mutations in the ABCC6 ABC-transporter are causative of pseudoxanthoma elasticum (PXE). The loss of functional ABCC6 protein in the basolateral membrane of the kidney and liver is putatively associated with altered secretion of a circulatory factor. As a result, systemic changes in elastic tissues are caused by progressive mineralization and degradation of elastic fibers. Premature arteriosclerosis, loss of skin and vascular tone, and a progressive loss of vision result from this ectopic mineralization. However, the identity of the circulatory factor and the specific role of ABCC6 in disease pathophysiology are not known. Though recessive loss-of-function alleles are associated with alterations in ABCC6 expression and function, the molecular pathologies associated with the majority of PXE-causing mutations are also not known. Sequence analysis of orthologous ABCC6 proteins indicates the C-terminal sequences are highly conserved and share high similarity to the PDZ sequences found in other ABCC subfamily members. Genetic testing of PXE patients suggests that at least one disease-causing mutation is located in a PDZ-like sequence at the extreme C-terminus of the ABCC6 protein. To evaluate the role of this C-terminal sequence in the biosynthesis and trafficking of ABCC6, a series of mutations were utilized to probe changes in ABCC6 biosynthesis, membrane stability and turnover. Removal of this PDZ-like sequence resulted in decreased steady-state ABCC6 levels, decreased cell surface expression and stability, and mislocalization of the ABCC6 protein in polarized cells. These data suggest that the conserved, PDZ-like sequence promotes the proper biosynthesis and trafficking of the ABCC6 protein.
References
[1]
Germain DP, Boutouyrie P, Laloux B, Laurent S (2003) Arterial remodeling and stiffness in patients with pseudoxanthoma elasticum. Arterioscler Thromb Vasc Biol 23: 836–841. doi: 10.1161/01.atv.0000067428.19031.28
[2]
Lebwohl M (1993) Images in clinical medicine. Pseudoxanthoma elasticum. N Engl J Med 329: 1240. doi: 10.1056/nejm199310213291706
[3]
Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, et al. (2000) Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 25: 228–231.
[4]
Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, et al. (2000) Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 25: 223–227. doi: 10.1038/76102
[5]
Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, et al. (2005) Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Hum Mutat 26: 235–248. doi: 10.1002/humu.20206
[6]
Schulz V, Hendig D, Szliska C, Gotting C, Kleesiek K (2005) Novel mutations in the ABCC6 gene of German patients with pseudoxanthoma elasticum. Hum Biol 77: 367–384. doi: 10.1353/hub.2005.0054
[7]
Plomp AS, Florijn RJ, Ten Brink J, Castle B, Kingston H, et al. (2008) ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones. Mol Vis 14: 118–124.
[8]
Jiang Q, Uitto J (2006) Pseudoxanthoma elasticum: a metabolic disease? J Invest Dermatol 126: 1440–1441. doi: 10.1038/sj.jid.5700267
[9]
Dean M, Rzhetsky A, Allikmets R (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 11: 1156–1166. doi: 10.1101/gr.gr-1649r
[10]
Moody JE, Millen L, Binns D, Hunt JF, Thomas PJ (2002) Cooperative, ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters. J Biol Chem 277: 21111–21114. doi: 10.1074/jbc.c200228200
[11]
Smith PC, Karpowich N, Millen L, Moody JE, Rosen J, et al. (2002) ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol Cell 10: 139–149. doi: 10.1016/s1097-2765(02)00576-2
[12]
Zaitseva J, Jenewein S, Jumpertz T, Holland IB, Schmitt L (2005) H662 is the linchpin of ATP hydrolysis in the nucleotide-binding domain of the ABC transporter HlyB. EMBO J 24: 1901–1910. doi: 10.1038/sj.emboj.7600657
[13]
Dawson RJ, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443: 180–185. doi: 10.1038/nature05155
[14]
Wilken S, Schmees G, Schneider E (1996) A putative helical domain in the MalK subunit of the ATP-binding-cassette transport system for maltose of Salmonella typhimurium (MalFGK2) is crucial for interaction with MalF and MalG. A study using the LacK protein of Agrobacterium radiobacter as a tool. Mol Microbiol 22: 655–666. doi: 10.1046/j.1365-2958.1996.d01-1724.x
[15]
Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, et al. (1993) Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 362: 160–164. doi: 10.1038/362160a0
[16]
Welsh MJ, Smith AE (1993) Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73: 1251–1254. doi: 10.1016/0092-8674(93)90353-r
[17]
Arlanov R, Porter A, Strand D, Brough R, Karpova D, et al. (2012) Functional characterization of protein variants of the human multidrug transporter ABCC2 by a novel targeted expression system in fibrosarcoma cells. Hum Mutat 33: 750–762. doi: 10.1002/humu.22041
[18]
Faletra F, Snider K, Shyng SL, Bruno I, Athanasakis E, et al.. (2012) Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: Clinical and functional characterization of two novel ABCC8 mutations. Gene.
[19]
Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (1995) Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269: 1737–1740. doi: 10.1126/science.7569905
[20]
Kim E, Niethammer M, Rothschild A, Jan YN, Sheng M (1995) Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378: 85–88. doi: 10.1038/378085a0
[21]
Azim AC, Knoll JH, Marfatia SM, Peel DJ, Bryant PJ, et al. (1995) DLG1: chromosome location of the closest human homologue of the Drosophila discs large tumor suppressor gene. Genomics 30: 613–616. doi: 10.1006/geno.1995.1286
[22]
Kocher O, Comella N, Gilchrist A, Pal R, Tognazzi K, et al. (1999) PDZK1, a novel PDZ domain-containing protein up-regulated in carcinomas and mapped to chromosome 1q21, interacts with cMOAT (MRP2), the multidrug resistance-associated protein. Lab Invest 79: 1161–1170.
[23]
Hegedus T, Sessler T, Scott R, Thelin W, Bakos E, et al. (2003) C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins. Biochem Biophys Res Commun 302: 454–461. doi: 10.1016/s0006-291x(03)00196-7
[24]
Hayashi H, Naoi S, Nakagawa T, Nishikawa T, Fukuda H, et al. (2012) Sorting nexin 27 interacts with multidrug resistance-associated protein 4 (MRP4) and mediates internalization of MRP4. J Biol Chem 287: 15054–15065. doi: 10.1074/jbc.m111.337931
[25]
Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, et al. (1998) 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: 8496–8501. doi: 10.1073/pnas.95.15.8496
[26]
Stiffler MA, Chen JR, Grantcharova VP, Lei Y, Fuchs D, et al. (2007) PDZ domain binding selectivity is optimized across the mouse proteome. Science 317: 364–369. doi: 10.1126/science.1144592
[27]
Haggie PM, Kim JK, Lukacs GL, Verkman AS (2006) Tracking of quantum dot-labeled CFTR shows near immobilization by C-terminal PDZ interactions. Mol Biol Cell 17: 4937–4945. doi: 10.1091/mbc.e06-08-0670
[28]
Cushing PR, Fellows A, Villone D, Boisguerin P, Madden DR (2008) The relative binding affinities of PDZ partners for CFTR: a biochemical basis for efficient endocytic recycling. Biochemistry 47: 10084–10098. doi: 10.1021/bi8003928
[29]
Kwon SH, Pollard H, Guggino WB (2007) Knockdown of NHERF1 enhances degradation of temperature rescued DeltaF508 CFTR from the cell surface of human airway cells. Cell Physiol Biochem 20: 763–772. doi: 10.1159/000110436
[30]
Mossessova E, Lima CD (2000) Ulp1-SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast. Mol Cell 5: 865–876. doi: 10.1016/s1097-2765(00)80326-3
[31]
Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, et al. (2004) Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J 23: 282–293. doi: 10.1038/sj.emboj.7600040
[32]
Thibodeau PH, Brautigam CA, Machius M, Thomas PJ (2005) Side chain and backbone contributions of Phe508 to CFTR folding. Nat Struct Mol Biol 12: 10–16. doi: 10.1038/nsmb881
[33]
Zhang L, Conway JF, Thibodeau PH (2012) Calcium-induced folding and stabilization of the Pseudomonas aeruginosa alkaline protease. J Biol Chem 287: 4311–4322. doi: 10.1074/jbc.m111.310300
[34]
Fulop K, Barna L, Symmons O, Zavodszky P, Varadi A (2009) Clustering of disease-causing mutations on the domain-domain interfaces of ABCC6. Biochem Biophys Res Commun 379: 706–709. doi: 10.1016/j.bbrc.2008.12.142
[35]
Hu X, Plomp A, Wijnholds J, Ten Brink J, van Soest S, et al. (2003) ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum. Eur J Hum Genet 11: 215–224. doi: 10.1038/sj.ejhg.5200953
[36]
Wegman JJ, Hu X, Tan H, Bergen AA, Trip MD, et al. (2005) Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype. Int J Cardiol 100: 389–393. doi: 10.1016/j.ijcard.2004.07.012
[37]
Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, et al. (2007) Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum. J Med Genet 44: 621–628. doi: 10.1136/jmg.2007.051094
[38]
Moyer BD, Denton J, Karlson KH, Reynolds D, Wang S, et al. (1999) A PDZ-interacting domain in CFTR is an apical membrane polarization signal. J Clin Invest 104: 1353–1361. doi: 10.1172/jci7453
[39]
Wong HC, Bourdelas A, Krauss A, Lee HJ, Shao Y, et al. (2003) Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell 12: 1251–1260. doi: 10.1016/s1097-2765(03)00427-1
[40]
Sun R, Fan H, Gao F, Lin Y, Zhang L, et al. (2012) Crystal structure of Arabidopsis Deg2 protein reveals an internal PDZ ligand locking the hexameric resting state. J Biol Chem 287: 37564–37569. doi: 10.1074/jbc.m112.394585
[41]
Le Saux O, Fulop K, Yamaguchi Y, Ilias A, Szabo Z, et al. (2011) Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. PLoS One 6: e24738. doi: 10.1371/journal.pone.0024738
[42]
Jin MS, Oldham ML, Zhang Q, Chen J (2012) Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 490: 566–569. doi: 10.1038/nature11448
[43]
Protasevich I, Yang Z, Wang C, Atwell S, Zhao X, et al. (2010) Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1. Protein Sci 19: 1917–1931. doi: 10.1002/pro.479
[44]
Bear CE, Duguay F, Naismith AL, Kartner N, Hanrahan JW, et al. (1991) Cl- channel activity in Xenopus oocytes expressing the cystic fibrosis gene. The Journal of biological chemistry 266: 19142–19145.
[45]
Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, et al. (1992) Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358: 761–764. doi: 10.1038/358761a0
[46]
Dorwart MR, Shcheynikov N, Baker JM, Forman-Kay JD, Muallem S, et al. (2008) Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3. J Biol Chem 283: 8711–8722. doi: 10.1074/jbc.m704328200
[47]
Zhou Z, Gong Q, January CT (1999) Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem 274: 31123–31126. doi: 10.1074/jbc.274.44.31123
[48]
Chen I, Howarth M, Lin W, Ting AY (2005) Site-specific labeling of cell surface proteins with biophysical probes using biotin ligase. Nat Methods 2: 99–104. doi: 10.1038/nmeth735
[49]
Balut CM, Gao Y, Murray SA, Thibodeau PH, Devor DC (2010) ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes. Am J Physiol Cell Physiol 299: C1015–1027. doi: 10.1152/ajpcell.00120.2010
[50]
Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, et al. (2010) The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem 285: 35825–35835. doi: 10.1074/jbc.m110.131623
[51]
Cui L, Aleksandrov L, Chang XB, Hou YX, He L, et al. (2007) Domain interdependence in the biosynthetic assembly of CFTR. J Mol Biol 365: 981–994. doi: 10.1016/j.jmb.2006.10.086
[52]
Du K, Lukacs GL (2009) Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell 20: 1903–1915. doi: 10.1091/mbc.e08-09-0950
[53]
Emi Y, Yasuda Y, Sakaguchi M (2012) A cis-acting five-amino-acid motif controls targeting of ABCC2 to the apical plasma membrane domain. J Cell Sci 125: 3133–3143. doi: 10.1242/jcs.099549
[54]
Milewski MI, Mickle JE, Forrest JK, Stafford DM, Moyer BD, et al. (2001) A PDZ-binding motif is essential but not sufficient to localize the C terminus of CFTR to the apical membrane. J Cell Sci 114: 719–726.
[55]
Noda Y, Horikawa S, Furukawa T, Hirai K, Katayama Y, et al. (2004) Aquaporin-2 trafficking is regulated by PDZ-domain containing protein SPA-1. FEBS Lett 568: 139–145. doi: 10.1016/j.febslet.2004.05.021
[56]
Maday S, Anderson E, Chang HC, Shorter J, Satoh A, et al. (2008) A PDZ-binding motif controls basolateral targeting of syndecan-1 along the biosynthetic pathway in polarized epithelial cells. Traffic 9: 1915–1924. doi: 10.1111/j.1600-0854.2008.00805.x
[57]
Harris MJ, Kuwano M, Webb M, Board PG (2001) Identification of the apical membrane-targeting signal of the multidrug resistance-associated protein 2 (MRP2/MOAT). J Biol Chem 276: 20876–20881. doi: 10.1074/jbc.m010566200
[58]
Emi Y, Nomura S, Yokota H, Sakaguchi M (2011) ATP-binding cassette transporter isoform C2 localizes to the apical plasma membrane via interactions with scaffolding protein. J Biochem 149: 177–189. doi: 10.1093/jb/mvq131
[59]
Gee HY, Noh SH, Tang BL, Kim KH, Lee MG (2011) Rescue of DeltaF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. Cell 146: 746–760. doi: 10.1016/j.cell.2011.07.021
[60]
Jansen RS, Kucukosmanoglu A, de Haas M, Sapthu S, Otero JA, et al. (2013) ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A 110: 20206–20211. doi: 10.1073/pnas.1319582110
