Phenylketonuria as a protein misfolding disease: The mutation pG46S in phenylalanine hydroxylase promotes self-association and fibril formation

Biochimica et Biophysica Acta - Molecular Basis of Disease

Volumn 1812, Issue 1, 2011, Pages 106-120

  Leandro, João ^a,b   Simonsen, Nina ^a   Saraste, Jaakko ^a   Leandro, Paula ^b   Flatmark, Torgeir ^a  

^a UNIVERSITY OF BERGEN   (Norway)

^b UNIVERSITY OF LISBON   (Portugal)

Author keywords

Chaperone; Fibril formation; PG46S; Phenylalanine hydroxylase; Phenylketonuria; Polymerization

Indexed keywords

CHAPERONE; HEAT SHOCK PROTEIN 40; HEAT SHOCK PROTEIN 70; HEAT SHOCK PROTEIN 90; OLIGOMER; OXYGENASE; PHENYLALANINE; PHENYLALANINE 4 MONOOXYGENASE; POLYMER;

ALPHA HELIX; ANIMAL CELL; ARTICLE; CONFORMATIONAL TRANSITION; ELECTRON MICROSCOPY; FIBER; IONIC STRENGTH; NONHUMAN; PH; PHENYLKETONURIA; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN PHOSPHORYLATION; STOICHIOMETRY; TEMPERATURE;

AMINO ACID SUBSTITUTION; BIOCATALYSIS; HEAT-SHOCK PROTEINS; HUMANS; HYDROGEN-ION CONCENTRATION; ISOQUINOLINES; MALTOSE-BINDING PROTEINS; MICROSCOPY, ELECTRON; MODELS, MOLECULAR; MUTAGENESIS, SITE-DIRECTED; MUTANT PROTEINS; MUTATION; OSMOLAR CONCENTRATION; PHENYLALANINE HYDROXYLASE; PHENYLKETONURIAS; PHOSPHORYLATION; PROTEIN CONFORMATION; PROTEIN FOLDING; PROTEIN MULTIMERIZATION; PROTEIN STRUCTURE, SECONDARY; PROTEIN STRUCTURE, TERTIARY; RECOMBINANT FUSION PROTEINS; SERINE; SUBSTRATE SPECIFICITY; TEMPERATURE;

EID: 78650281988     PISSN: 09254439     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbadis.2010.09.015     Document Type: Article

References (77)

1. Hoang L., Byck S., Prevost L., Scriver C.R. PAH Mutation Analysis Consortium Database: a database for disease-producing and other allelic variation at the human PAH locus. Nucleic Acids Res. 1996, 24:127-131.
2. Scriver C.R., Waters P.J. Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet. 1999, 15:267-272.
3. Flatmark T., Knappskog P.M., Bjørgo E., Martínez A. Molecular characterization of disease related mutant forms of human phenylalanine hydroxylase and tyrosine hydroxylase. Chemistry and Biology of Pteridines and Folates 1997, vol. 8:503-508. Blackwell Science, Berlin.
4. Waters P.J. How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression. Hum. Mutat. 2003, 21:357-369.
5. Gregersen N., Bross P., Andresen B.S., Pedersen C.B., Corydon T.J., Bolund L. The role of chaperone-assisted folding and quality control in inborn errors of metabolism: protein folding disorders. J. Inherit. Metab. Dis. 2001, 24:189-212.
6. Bjørgo E., Knappskog P.M., Martinez A., Stevens R.C., Flatmark T. Partial characterization and three-dimensional-structural localization of eight mutations in exon 7 of the human phenylalanine hydroxylase gene associated with phenylketonuria. Eur. J. Biochem. 1998, 257:1-10.
7. Erlandsen H., Stevens R.C. The structural basis of phenylketonuria. Mol. Genet. Metab. 1999, 68:103-125.
8. Flatmark T., Stevens R.C. Structural insight into the aromatic amino acid hydroxylases and their disease-related mutant forms. Chem. Rev. 1999, 99:2137-2160.
9. Gersting S.W., Kemter K.F., Staudigl M., Messing D.D., Danecka M.K., Lagler F.B., Sommerhoff C.P., Roscher A.A., Muntau A.C. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am. J. Hum. Genet. 2008, 83:5-17.
10. Fox J.D., Kapust R.B., Waugh D.S. Single amino acid substitutions on the surface of Escherichia coli maltose-binding protein can have a profound impact on the solubility of fusion proteins. Protein Sci. 2001, 10:622-630.
11. Kapust R.B., Waugh D.S. Escherichia coli maltose-binding protein is uncommonly effective at promoting the solubility of polypeptides to which it is fused. Protein Sci. 1999, 8:1668-1674.
12. Eiken H.G., Knappskog P.M., Apold J., Flatmark T. PKU mutation G46S is associated with increased aggregation and degradation of the phenylalanine hydroxylase enzyme. Hum. Mutat. 1996, 7:228-238.
13. Pey A.L., Stricher F., Serrano L., Martinez A. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am. J. Hum. Genet. 2007, 81:1006-1024.
14. Miranda F.F., Teigen K., Thorolfsson M., Svebak R.M., Knappskog P.M., Flatmark T., Martinez A. Phosphorylation and mutations of Ser(16) in human phenylalanine hydroxylase. Kinetic and structural effects. J. Biol. Chem. 2002, 277:40937-40943.
15. Chehin R., Thorolfsson M., Knappskog P.M., Martinez A., Flatmark T., Arrondo J.L., Muga A. Domain structure and stability of human phenylalanine hydroxylase inferred from infrared spectroscopy. FEBS Lett. 1998, 422:225-230.
16. Teigen K., Martinez A. Probing cofactor specificity in phenylalanine hydroxylase by molecular dynamics simulations. J. Biomol. Struct. Dyn. 2003, 20:733-740.
17. Martinez A., Knappskog P.M., Olafsdottir S., Døskeland A.P., Eiken H.G., Svebak R.M., Bozzini M., Apold J., Flatmark T. Expression of recombinant human phenylalanine hydroxylase as fusion protein in Escherichia coli circumvents proteolytic degradation by host cell proteases. Isolation and characterization of the wild-type enzyme. Biochem. J. 1995, 306:589-597.
18. Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976, 72:248-254.
19. Bjørgo E., de Carvalho R.M., Flatmark T. A comparison of kinetic and regulatory properties of the tetrameric and dimeric forms of wild-type and Thr427->Pro mutant human phenylalanine hydroxylase: contribution of the flexible hinge region Asp425-Gln429 to the tetramerization and cooperative substrate binding. Eur. J. Biochem. 2001, 268:997-1005.
20. Knappskog P.M., Flatmark T., Aarden J.M., Haavik J., Martinez A. Structure/function relationships in human phenylalanine hydroxylase. Effect of terminal deletions on the oligomerization, activation and cooperativity of substrate binding to the enzyme. Eur. J. Biochem. 1996, 242:813-821.
21. Døskeland A.P., Martinez A., Knappskog P.M., Flatmark T. Phosphorylation of recombinant human phenylalanine hydroxylase: effect on catalytic activity, substrate activation and protection against non-specific cleavage of the fusion protein by restriction protease. Biochem. J. 1996, 313(Pt 2):409-414.
22. Laemmli U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970, 227:680-685.
23. Eisert R., Felau L., Brown L.R. Methods for enhancing the accuracy and reproducibility of Congo red and thioflavin T assays. Anal. Biochem. 2006, 353:144-146.
24. Aukrust I., Evensen L., Hollås H., Berven F., Atkinson R.A., Travé G., Flatmark T., Vedeler A. Engineering, biophysical characterisation and binding properties of a soluble mutant form of annexin A2 domain IV that adopts a partially folded conformation. J. Mol. Biol. 2006, 363:469-481.
25. Døskeland A.P., Døskeland S.O., Øgreid D., Flatmark T. The effect of ligands of phenylalanine 4-monooxygenase on the cAMP-dependent phosphorylation of the enzyme. J. Biol. Chem. 1984, 259:11242-11248.
26. LiCata V.J., Allewell N.M. Is substrate inhibition a consequence of allostery in aspartate transcarbamylase?. Biophys. Chem. 1997, 64:225-234.
27. Solstad T., Flatmark T. Microheterogeneity of recombinant human phenylalanine hydroxylase as a result of nonenzymatic deamidations of labile amide containing amino acids. Effects on catalytic and stability properties. Eur. J. Biochem. 2000, 267:6302-6310.
28. Parthiban V., Gromiha M.M., Schomburg D. CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res. 2006, 34:W239-W242.
29. Benedix A., Becker C.M., de Groot B.L., Caflisch A., Bockmann R.A. Predicting free energy changes using structural ensembles. Nat. Methods 2009, 6:3-4.
30. Lacroix E., Viguera A.R., Serrano L. Elucidating the folding problem of alpha-helices: local motifs, long-range electrostatics, ionic-strength dependence and prediction of NMR parameters. J. Mol. Biol. 1998, 284:173-191.
31. Flores S.C., Keating K.S., Painter J., Morcos F., Nguyen K., Merritt E.A., Kuhn L.A., Gerstein M.B. HingeMaster: normal mode hinge prediction approach and integration of complementary predictors. Proteins 2008, 73:299-319.
32. Erlandsen H., Fusetti F., Martinez A., Hough E., Flatmark T., Stevens R.C. Crystal structure of the catalytic domain of human phenylalanine hydroxylase reveals the structural basis for phenylketonuria. Nat. Struct. Biol. 1997, 4:995-1000.
33. Fusetti F., Erlandsen H., Flatmark T., Stevens R.C. Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. J. Biol. Chem. 1998, 273:16962-16967.
34. Kobe B., Jennings I.G., House C.M., Michell B.J., Goodwill K.E., Santarsiero B.D., Stevens R.C., Cotton R.G., Kemp B.E. Structural basis of autoregulation of phenylalanine hydroxylase. Nat. Struct. Biol. 1999, 6:442-448.
35. O'Neil K.T., DeGrado W.F. A thermodynamic scale for the helix-forming tendencies of the commonly occurring amino acids. Science 1990, 250:646-651.
36. Evans C.G., Wisen S., Gestwicki J.E. Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J. Biol. Chem. 2006, 281:33182-33191.
37. Solstad T., Stokka A.J., Andersen O.A., Flatmark T. Studies on the regulatory properties of the pterin cofactor and dopamine bound at the active site of human phenylalanine hydroxylase. Eur. J. Biochem. 2003, 270:981-990.
38. Aguado C., Perez B., Ugarte M., Desviat L.R. Analysis of the effect of tetrahydrobiopterin on PAH gene expression in hepatoma cells. FEBS Lett. 2006, 580:1697-1701.
39. Perez B., Desviat L.R., Gomez-Puertas P., Martinez A., Stevens R.C., Ugarte M. Kinetic and stability analysis of PKU mutations identified in BH4-responsive patients. Mol. Genet. Metab. 2005, 86(Suppl 1):S11-S16.
40. Scriver C.R. The PAH gene, phenylketonuria, and a paradigm shift. Hum. Mutat. 2007, 28:831-845.
41. Pey A.L., Ying M., Cremades N., Velazquez-Campoy A., Scherer T., Thöny B., Sancho J., Martinez A. Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. J. Clin. Invest. 2008, 118:2858-2867.
42. Leandro P., Gomes C.M. Protein misfolding in conformational disorders: rescue of folding defects and chemical chaperoning. Mini Rev. Med. Chem. 2008, 8:901-911.
43. Martinez A., Calvo A.C., Teigen K., Pey A.L. Rescuing proteins of low kinetic stability by chaperones and natural ligands phenylketonuria, a case study. Prog. Mol. Biol. Transl. Sci. 2008, 83:89-134.
44. Semisotnov G.V., Rodionova N.A., Razgulyaev O.I., Uversky V.N., Gripas A.F., Gilmanshin R.I. Study of the "molten globule" intermediate state in protein folding by a hydrophobic fluorescent probe. Biopolymers 1991, 31:119-128.
45. Dykes G.W., Crepeau R.H., Edelstein S.J. Three-dimensional reconstruction of the 14-filament fibers of hemoglobin S. J. Mol. Biol. 1979, 130:451-472.
46. Kure S., Hou D.C., Ohura T., Iwamoto H., Suzuki S., Sugiyama N., Sakamoto O., Fujii K., Matsubara Y., Narisawa K. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J. Pediatr. 1999, 135:375-378.
47. Boveda M.D., Couce M.L., Castineiras D.E., Cocho J.A., Perez B., Ugarte M., Fraga J.M. The tetrahydrobiopterin loading test in 36 patients with hyperphenylalaninaemia: evaluation of response and subsequent treatment. J. Inherit. Metab. Dis. 2007, 30:812.
48. Zurfluh M.R., Zschocke J., Lindner M., Feillet F., Chery C., Burlina A., Stevens R.C., Thöny B., Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum. Mutat. 2008, 29:167-175.
49. Leandro P., Lechner M.C., Tavares de Almeida I., Konecki D. Glycerol increases the yield and activity of human phenylalanine hydroxylase mutant enzymes produced in a prokaryotic expression system. Mol. Genet. Metab. 2001, 73:173-178.
50. Nascimento C., Leandro J., Tavares de Almeida I., Leandro P. Modulation of the activity of newly synthesized human phenylalanine hydroxylase mutant proteins by low-molecular-weight compounds. Protein J. 2008, 27:392-400.
51. Song J.L., Chuang D.T. Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chain alpha-ketoacid decarboxylase in maple syrup urine disease. J. Biol. Chem. 2001, 276:40241-40246.
52. Uversky V.N., Li J., Fink A.L. Trimethylamine-N-oxide-induced folding of alpha-synuclein. FEBS Lett. 2001, 509:31-35.
53. Yang D.S., Yip C.M., Huang T.H., Chakrabartty A., Fraser P.E. Manipulating the amyloid-beta aggregation pathway with chemical chaperones. J. Biol. Chem. 1999, 274:32970-32974.
54. Ehrnhoefer D.E., Bieschke J., Boeddrich A., Herbst M., Masino L., Lurz R., Engemann S., Pastore A., Wanker E.E. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat. Struct. Mol. Biol. 2008, 15:558-566.
55. Khurana R., Coleman C., Ionescu-Zanetti C., Carter S.A., Krishna V., Grover R.K., Roy R., Singh S. Mechanism of thioflavin T binding to amyloid fibrils. J. Struct. Biol. 2005, 151:229-238.
56. Ivanova M.I., Thompson M.J., Eisenberg D. A systematic screen of beta(2)-microglobulin and insulin for amyloid-like segments. Proc. Natl. Acad. Sci. U. S. A. 2006, 103:4079-4082.
57. Bennett M.J., Sawaya M.R., Eisenberg D. Deposition diseases and 3D domain swapping. Structure 2006, 14:811-824.
58. Ferrone F.A., Hofrichter J., Eaton W.A. Kinetics of sickle hemoglobin polymerization. I. Studies using temperature-jump and laser photolysis techniques. J. Mol. Biol. 1985, 183:591-610.
59. Dykes G., Crepeau R.H., Edelstein S.J. Three-dimensional reconstruction of the fibres of sickle cell haemoglobin. Nature 1978, 272:506-510.
60. Stokka A.J., Carvalho R.N., Barroso J.F., Flatmark T. Probing the role of crystallographically defined/predicted hinge-bending regions in the substrate-induced global conformational transition and catalytic activation of human phenylalanine hydroxylase by single-site mutagenesis. J. Biol. Chem. 2004, 279:26571-26580.
61. Thorolfsson M., Ibarra-Molero B., Fojan P., Petersen S.B., Sanchez-Ruiz J.M., Martinez A. l-phenylalanine binding and domain organization in human phenylalanine hydroxylase: a differential scanning calorimetry study. Biochemistry 2002, 41:7573-7585.
62. Fernandez-Escamilla A.M., Rousseau F., Schymkowitz J., Serrano L. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat. Biotechnol. 2004, 22:1302-1306.
63. Solstad T., Carvalho R.N., Andersen O.A., Waidelich D., Flatmark T. Deamidation of labile asparagine residues in the autoregulatory sequence of human phenylalanine hydroxylase. Eur. J. Biochem. 2003, 270:929-938.
64. Pey A.L., Martinez A. The activity of wild-type and mutant phenylalanine hydroxylase and its regulation by phenylalanine and tetrahydrobiopterin at physiological and pathological concentrations: an isothermal titration calorimetry study. Mol. Genet. Metab. 2005, 86(Suppl 1):S43-S53.
65. Buell A.K., Tartaglia G.G., Birkett N.R., Waudby C.A., Vendruscolo M., Salvatella X., Welland M.E., Dobson C.M., Knowles T.P. Position-dependent electrostatic protection against protein aggregation. Chembiochem 2009, 10:1309-1312.
66. Chiti F., Stefani M., Taddei N., Ramponi G., Dobson C.M. Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 2003, 424:805-808.
67. DuBay K.F., Pawar A.P., Chiti F., Zurdo J., Dobson C.M., Vendruscolo M. Prediction of the absolute aggregation rates of amyloidogenic polypeptide chains. J. Mol. Biol. 2004, 341:1317-1326.
68. Gamez A., Perez B., Ugarte M., Desviat L.R. Expression analysis of phenylketonuria mutations. Effect on folding and stability of the phenylalanine hydroxylase protein. J. Biol. Chem. 2000, 275:29737-29742.
69. Pey A.L., Desviat L.R., Gamez A., Ugarte M., Perez B. Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum. Mutat. 2003, 21:370-378.
70. Døskeland A.P., Flatmark T. Conjugation of phenylalanine hydroxylase with polyubiquitin chains catalysed by rat liver enzymes. Biochim. Biophys. Acta 2001, 1547:379-386.
71. Baker R.E., Shiman R. Measurement of phenylalanine hydroxylase turnover in cultured hepatoma cells. J. Biol. Chem. 1979, 254:9633-9639.
72. Kopitz J., Kisen G.O., Gordon P.B., Bohley P., Seglen P.O. Nonselective autophagy of cytosolic enzymes by isolated rat hepatocytes. J. Cell Biol. 1990, 111:941-953.
73. Kirkin V., McEwan D.G., Novak I., Dikic I. A role for ubiquitin in selective autophagy. Mol. Cell 2009, 34:259-269.
74. Kleppe R., Uhlemann K., Knappskog P.M., Haavik J. Urea-induced denaturation of human phenylalanine hydroxylase. J. Biol. Chem. 1999, 274:33251-33258.
75. Leandro J., Nascimento C., de Almeida I.T., Leandro P. Co-expression of different subunits of human phenylalanine hydroxylase: evidence of negative interallelic complementation. Biochim. Biophys. Acta 2006, 1762:544-550.
76. Kraulis P.J. Molscript - a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 1991, 24:946-950.
77. Delano W.L. The PyMOL Molecular Graphics System 2002, DeLano Scientific, San Carlos, USA.