Scalable production in human cells and biochemical characterization of full-length normal and mutant huntingtin

PLoS ONE

Volumn 10, Issue 3, 2015, Pages

  Huang, Bin ^a   Lucas, Tanja ^a   Kueppers, Claudia ^a   Dong, Xiaomin ^a   Krause, Maike ^b   Bepperling, Alexander ^b   Buchner, Johannes ^b   Voshol, Hans ^c   Weiss, Andreas ^c,d   Gerrits, Bertran ^c   Kochanek, Stefan ^a  

^a UNIVERSITY OF ULM   (Germany)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^c NOVARTIS PHARMA AG   (Switzerland)

^d IRBM   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOVIRUS VECTOR; ALANINE; DIMER; DOXYCYCLINE; HUNTINGTIN; METHIONINE; OLIGOMER; HTT PROTEIN, HUMAN; NERVE PROTEIN; RECOMBINANT PROTEIN;

AMINO TERMINAL SEQUENCE; ARTICLE; CELL LINE; CONTROLLED STUDY; DIMERIZATION; HUMAN; HUMAN CELL; MUTANT; OLIGOMERIZATION; PROTEIN ACETYLATION; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN SYNTHESIS; VIRAL GENE DELIVERY SYSTEM; CHEMISTRY; CIRCULAR DICHROISM; GENETICS; METABOLISM; MUTATION; PHOSPHORYLATION; PROTEIN SECONDARY STRUCTURE;

ADENOVIRIDAE; SOLENOIDEA;

CELL LINE; CIRCULAR DICHROISM; DOXYCYCLINE; HUMANS; HUNTINGTIN PROTEIN; MUTATION; NERVE TISSUE PROTEINS; PHOSPHORYLATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEIN STRUCTURE, SECONDARY; RECOMBINANT PROTEINS;

EID: 84925728810     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0121055     Document Type: Article

References (88)

1. Harper PS. Huntington's Disease. Philiadelphia: W. B. Saunders; 1991.
2. Bates G, Harper PS, Jones L. Huntington's Disease. Oxford: Oxford University Press; 2002.
3. DiFiglia M, Sapp E, Chase K.O., Davies SW, Bates GP, Vonsattel JP, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997; 277:1990-1993. PMID: 9302293
4. Davies SW, Turmaine M, Cozens B.A., DiFiglia M., Sharp AH, Ross CA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997; 90:537-548. PMID: 9267033
5. Walker FO. Huntington's Disease. Semin Neurol. 2007; 27:143-150. PMID: 17390259
6. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993; 72:971-983. PMID: 8458085
7. Rubinsztein DC, Leggo J, Coles R., Almqvist E, Biancalana V, Cassiman J.J., et al. Phenotypiccharacterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996; 59:16-22. PMID: 8659522
8. Semaka A, Hayden MR. Evidence-based genetic counselling implications for Huntington disease intermediate allele predictive test results. Clin Genet. 2014; 85:303-311. doi: 10.1111/cge.12324 PMID: 24256063
9. Potter NT, Spector EB, Prior TW. Technical standards and guidelines for Huntington disease testing. Genet Med. 2004; 6:61-65. PMID: 14726813
10. Mangiarini L, Sathasivam K, Seller M., Cozens B, Harper A, Hetherington C., et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996; 87:493-506. PMID: 8898202
11. Ordway JM, Tallaksen-Greene S, Gutekunst C.A., Bernstein EM, Cearley JA, Wiener HW, et al. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell. 1997; 91:753-763. PMID: 9413985
12. Lin CH, Tallaksen-Greene S, Chien W.M., Cearley JA, Jackson WS, Crouse AB, et al. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum Mol Genet. 2001; 10:137-144. PMID: 11152661
13. Ishiguro H, Yamada K, Sawada H., Nishii K, Ichino N, Sawada M., et al. Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene. J Neurosci Res. 2001; 65:289-297. PMID: 11494364
14. Zuccato C, Ciammola A, Rigamonti D., Leavitt BR, Goffredo D, Conti L, et al. Loss of huntingtin-mediat-ed BDNF gene transcription in Huntington's disease. Science. 2001; 293:493-498. PMID: 11408619
15. Zuccato C, Tartari M, Crotti A., Goffredo D, Valenza M, Conti L., et al. Huntingtin interacts with REST/ NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet. 2003; 35:76-83. PMID: 12881722
16. Borrell-Pages M, Zala D, Humbert S., Saudou F. Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies. Cell Mol Life Sci. 2006; 63:2642-2660. PMID: 17041811
17. Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011; 10:83-98. doi: 10.1016/S1474-4422(10)70245-3 PMID: 21163446
18. Harjes P, Wanker EE. The hunt for huntingtin function: interaction partnerstell many different stories. Trends Biochem Sci. 2003; 28:425-433. PMID: 12932731
19. Li SH, Li XJ. Huntingtin and its role in neuronal degeneration. Neuroscientist. 2004; 10:467-475. PMID: 15359012
20. Caviston JP, Holzbaur EL. Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol. 2009; 19:147-155. doi: 10.1016/j.tcb.2009.01.005 PMID: 19269181
21. Mochel F, Haller RG. Energy deficit in Huntington disease: why it matters. J Clin Invest. 2011; 121: 493-499. doi: 10.1172/JCI45691 PMID: 21285522
22. Zuccato C, Cattaneo E. Normal Function of Huntingtin. In: Bates GP, Tabrizi SJ, Jones L, editors. Huntington's Disease. Oxford: Oxford University Press; 2014. p. 243-273.
23. Andrade MA, Bork P. HEAT repeats in the Huntington's disease protein. Nat Genet. 1995; 11:115-116. PMID: 7550332
24. Groves MR, Barford D. Topological characteristics of helical repeat proteins. CurrOpin Struct Biol. 1999; 9:383-389. PMID: 10361086
25. Takano H, Gusella JF. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC Neurosci. 2002; 3:15. PMID: 12379151
26. Li W, Serpell LC, Carter W.J., Rubinsztein DC, Huntington JA. Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein. J Biol Chem. 2006; 281:15916-15922. PMID: 16595690
27. Seong IS, Woda JM, Song J.J., Lloret A., Abeyrathne PD, Woo CJ, et al. Huntingtin facilitates polycomb repressive complex 2. Hum Mol Genet. 2010; 19:573-583. doi: 10.1093/hmg/ddp524 PMID: 19933700
28. Huang B, Schiefer J, Sass C., Landwehrmeyer GB, Kosinski CM, Kochanek S. High-capacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in vivo. Hum Gene Ther. 2007; 18:303-311. PMID: 17472569
29. Palmer D, Ng P. Improved system for helper-dependent adenoviral vector production. Mol Ther. 2003; 8:846-852. PMID: 14599819
30. Parks RJ, Chen L, Anton M., Sankar U, Rudnicki MA, Graham FL. A helper-dependent adenovirus vector system: removal of helper virus by Cre-mediated excision of the viral packaging signal. Proc Natl Acad Sci U S A. 1996; 93:13565-13570. PMID: 8942974
31. Schiedner G, Morral N, Parks R.J., Wu Y., Koopmans SC, Langston C, et al. Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat Genet. 1998; 18:180-183. PMID: 9462752
32. Kreppel F, Biermann V, Kochanek S., Schiedner G. A DNA-based method to assay total and infectious particle contents and helper virus contamination in high-capacity adenoviral vector preparations. Hum Gene Ther. 2002; 13:1151-1156. PMID: 12133268
33. Sambrook J, Russell DW. Molecular Cloning: ALaboratory Manual. NewYork: Cold Spring Harbour Laboratory Press; 2001.
34. Laue T, Shah B, Ridgeway T., Pelleiter S. Computer-aided interpretation of analytical sedimentation data of proteins. In: Harding S, Rowe A, Horton J, editors. Analytical ultracentifugation in biochemistry and polymer science. Cambridge: Royal Society of Chemistry; 1992. p. 90-125.
35. Schuck P. Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling. Biophys J. 2000; 78:1606-1619. PMID: 10692345
36. Wittig I, Karas M, Schagger H. High resolution clear native electrophoresis for in-gel functional assays and fluorescence studies of membrane protein complexes. Mol Cell Proteomics. 2007; 6:1215-1225. PMID: 17426019
37. Whitmore L, Wallace BA. Protein secondary structure analyses from circular dichroism spectroscopy: methods and reference databases. Biopolymers. 2008; 89:392-400. PMID: 17896349
38. Erickson HP. Size and shape of protein molecules at the nanometer level determined by sedimentation, gel filtration, and electron microscopy. Biol Proced Online. 2009; 11:32-51. doi: 10.1007/s12575-009-9008-x PMID: 19495910
39. Siegel LM, Monty KJ. Determination of molecular weights and frictional ratios of proteins in impure systems by use of gel filtration and density gradient centrifugation. Application to crude preparations of sulfite and hydroxylamine reductases. Biochim Biophys Acta. 1966; 112:346-362. PMID: 5329026
40. Keller A, Nesvizhskii AI, Kolker E, Aebersold R. Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Anal Chem. 2002; 74:5383-5392. PMID: 12403597
41. Nesvizhskii AI, Keller A, Kolker E., Aebersold R. A statistical model for identifying proteins by tandem mass spectrometry. Anal Chem. 2003; 75:4646-4658. PMID: 14632076
42. Gossen M, Freundlieb S, Bender G., Muller G, Hillen W, Bujard H. Transcriptional activation by tetracyclines in mammalian cells. Science. 1995; 268:1766-1769. PMID: 7792603
43. Humbert S, Bryson EA, Cordelieres F.P., Connors NC, Datta SR, Finkbeiner S, et al. The IGF-1/Aktpathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell. 2002; 2:831-837. PMID: 12062094
44. Rangone H, Poizat G, Troncoso J., Ross CA, MacDonald ME, Saudou F, et al. The serum- and glucocorticoid-induced kinase SGK inhibits mutant huntingtin-induced toxicity by phosphorylating serine 421 of huntingtin. Eur J Neurosci. 2004; 19:273-279. PMID: 14725621
45. Luo S, Vacher C, Davies J.E., Rubinsztein DC. Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol. 2005; 169:647-656. PMID: 15911879
46. Schilling B, Gafni J, Torcassi C., Cong X, Row RH, LaFevre-Bernt MA, et al. Huntingtin phosphorylation sites mapped by mass spectrometry. Modulation of cleavage and toxicity. J Biol Chem. 2006; 281:23686-23697. PMID: 16782707
47. Anne SL, Saudou F, Humbert S. Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J Neurosci. 2007; 27:7318-7328. PMID: 17611284
48. Zala D, Colin E, Rangone H., Liot G, Humbert S, Saudou F. Phosphorylation of mutant huntingtin at S421 restores anterograde and retrograde transport in neurons. Hum Mol Genet. 2008; 17:3837-3846. doi: 10.1093/hmg/ddn281 PMID: 18772195
49. Colin E, Zala D, Liot G., Rangone H, Borrell-Pages M, Li XJ, et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. Emboj. 2008; 27:2124-2134. doi: 10.1038/emboj.2008.133 PMID: 18615096
50. Aiken CT, Steffan JS, Guerrero C.M., Khashwji H., Lukacsovich T, Simmons D, et al. Phosphorylation of threonine 3: implications for Huntingtin aggregation and neurotoxicity. J Biol Chem. 2009; 284: 29427-29436. doi: 10.1074/jbc.M109.013193 PMID: 19710014
51. Ehrnhoefer DE, Sutton L, Hayden MR. Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist. 2011; 17:475-492. doi: 10.1177/1073858410390378 PMID:21311053
52. Shaw G, Morse S, Ararat M., Graham FL. Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. Faseb J. 2002; 16:869-871. PMID: 11967234
53. Warby SC, Chan EY, Metzler M, Gan L., Singaraja RR, Crocker SF, et al. Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo. Hum Mol Genet. 2005; 14:1569-1577. PMID: 15843398
54. Xia Q, Cheng D, Duong D.M., Gearing M., Lah JJ, Levey AI, et al. Phosphoproteomic analysis of human brain by calcium phosphate precipitation and mass spectrometry. J Proteome Res. 2008; 7:2845-2851. doi: 10.1021/pr8000496 PMID: 18510355
55. Dephoure N, Zhou C, Villen J., Beausoleil SA, Bakalarski CE, Elledge SJ, et al. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci USA. 2008; 105:10762-10767. doi: 10.1073/pnas. 0805139105 PMID: 18669648
56. Moritz A, Li Y, Guo A., Villen J, Wang Y, MacNeill J., et al. Akt-RSK-S6 kinase signaling networks activated by oncogenic receptor tyrosine kinases. Sci Signal. 2010; 3:ra64. doi: 10.1126/scisignal.2000998 PMID: 20736484
57. Phanstiel DH, Brumbaugh J, Wenger C.D., Tian S., Probasco MD, Bailey DJ, et al. Proteomic and phosphoproteomic comparison of human ES and iPS cells. Nat Methods. 2011; 8:821-827. doi: 10.1038/ nmeth.1699 PMID: 21983960
58. Dong G, Callegari E, Gloeckner C.J., Ueffing M., Wang H. Mass spectrometric identification of novel posttranslational modification sites in Huntingtin. Proteomics. 2012; 12:2060-2064. doi: 10.1002/pmic. 201100380 PMID: 22623107
59. Hornbeck PV, Kornhauser JM, Tkachev S, Zhang B., Skrzypek E, Murray B, et al. PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined posttranslational modifications in man and mouse. Nucleic Acids Res. 2012; 40:D261-270. URL: www.phosphosite.org/proteinAction.do?id=1292&showAllSites=true. Accessed 23 December 2014. doi: 10.1093/nar/gkr1122 PMID: 22135298
60. Fournier D, Palidwor GA, Shcherbinin S, Szengel A., Schaefer MH, Perez-Iratxeta C, et al. Functional and genomic analyses of alpha-solenoid proteins. PLoSOne. 2013; 8:e79894. URL: http://cbdm.mdcberlin.de/~ard2. Accessed October 10 2014. doi: 10.1371/journal.pone.0079894 PMID: 24278209
61. Rost B, Sander C, Schneider R. PHD-an automatic mail server for protein secondary structure prediction. ComputAppl Biosci. 1994; 10:53-60. PMID: 8193956
62. DiFiglia M, Sapp E, Chase K., Schwarz C, Meloni A, Young C., et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. 1995; 14:1075-1081. PMID: 7748555
63. Velier J, Kim M, Schwarz C., Kim TW, Sapp E, Chase K, et al. Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways. Exp Neurol. 1998; 152:34-40. PMID: 9682010
64. McMahon HT, Mills IG. COP and clathrin-coated vesicle budding: different pathways, common approaches. CurrOpin Cell Biol. 2004; 16:379-391. PMID: 15261670
65. Wu LG. Kinetic regulation of vesicle endocytosis at synapses. Trends Neurosci. 2004; 27:548-554. PMID: 15331237
66. Rohrbough J, Broadie K. Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci. 2005; 6: 139-150. PMID: 15685219
67. Suopanki J, Gotz C, Lutsch G., Schiller J, Harjes P, Herrmann A., et al. Interaction of huntingtin fragments with brain membranes-clues to early dysfunction in Huntington's disease. J Neurochem. 2006; 96:870-884. PMID: 16405500
68. Hilditch-Maguire P, Trettel F, Passani L.A., Auerbach A., Persichetti F, MacDonald ME. Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet. 2000; 9:2789-2797. PMID: 11092755
69. Gunawardena S, Her LS, Brusch R.G., Laymon RA, Niesman IR, Gordesky-Gold B, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron. 2003; 40:25-40. PMID: 14527431
70. Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre J.P., Rangone H., Cordelieres FP, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004; 118:127-138. PMID: 15242649
71. Pal A, Severin F, Lommer B., Shevchenko A, Zerial M. Huntingtin-HAP40 complex is a novel Rab5 ef-fectorthat regulates early endosome motility and is up-regulated in Huntington's disease. J Cell Biol. 2006; 172:605-618. PMID: 16476778
72. del Toro D, Alberch J, Lazaro-Dieguez F, Martin-Ibanez R, Xifro X, Egea G., et al. Mutant huntingtin impairs post-Golgi trafficking to lysosomes by delocalizing optineurin/Rab8 complex from the Golgi apparatus. Mol Biol Cell. 2009; 20:1478-1492. doi: 10.1091/mbc.E08-07-0726 PMID: 19144827
73. Atwal RS, Xia J, Pinchev D., Taylor J, Epand RM, Truant R. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet. 2007; 16:2600-2615. PMID: 17704510
74. Kegel KB, Sapp E, Yoder J., Cuiffo B, Sobin L, Kim Y.J., et al. Huntingtin associates with acidic phospholipids at the plasma membrane. J Biol Chem. 2005; 280:36464-36473. PMID: 16085648
75. Yanai A, Huang K, Kang R., Singaraja RR, Arstikaitis P, Gan L, et al. Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci. 2006; 9:824-831. PMID: 16699508
76. Wetzel R, Mishra R. Structural Biology: Order, Disorder, and Conformationa Flux. In: Bates GP, Tabrizi SJ, Jones L, editors. Huntington's Disease. Oxford: Oxford University Press; 2014.
77. Palidwor GA, Shcherbinin S, Huska M.R., Rasko T., Stelzl U, Arumughan A, et al. Detection of alpha-rod protein repeats using a neural network and application to huntingtin. PLoSComputBiol. 2009; 5: e1000304. doi: 10.1371/journal.pcbi.1000304 PMID: 19282972
78. Goldenberg SJ, Cascio TC, Shumway S.D., Garbutt KC, Liu J, Xiong Y, et al. Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubi-quitin ligases. Cell. 2004; 119:517-528. PMID: 15537541
79. Groves MR, Hanlon N, Turowski P., Hemmings BA, Barford D. The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell. 1999; 96:99-110. PMID: 9989501
80. Vetter IR, Arndt A, Kutay U., Gorlich D, Wittinghofer A. Structural view of the Ran-Importin beta interaction at 2.3 A resolution. Cell. 1999; 97:635-646. PMID: 10367892
81. Chook YM, Blobel G. Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp. Nature. 1999; 399:230-237. PMID: 10353245
82. Tartari M, Gissi C, LoSardo V., Zuccato C, Picardi E, Pesole G., et al. Phylogenetic comparison of huntingtin homologues reveals the appearance of a primitive polyQ in sea urchin. Mol Biol EVol. 2008; 25:330-338. PMID: 18048403
83. Warby SC, Doty CN, Graham R.K., Carroll JB, Yang YZ, Singaraja RR, et al. Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet. 2008; 17:2390-2404. doi: 10.1093/hmg/ddn139 PMID: 18445618
84. Thakur AK, Jayaraman M, Mishra R., Thakur M, Chellgren VM, Byeon I.J., et al. Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism. Nat Struct Mol Biol. 2009; 16:380-389. doi: 10.1038/nsmb.1570 PMID: 19270701
85. Sivanandam VN, Jayaraman M, Hoop C.L., Kodali R., Wetzel R, van der Wel PC. The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils. J Am Chem Soc. 2011; 133:4558-4566. doi: 10.1021/ja110715f PMID: 21381744
86. Wetzel R. Physical chemistry of polyglutamine: intriguing tales of a monotonous sequence. J Mol Biol. 2012; 421:466-490. doi: 10.1016/j.jmb.2012.01.030 PMID: 22306404
87. Starheim KK, Gevaert K, Arnesen T. Protein N-terminal acetyltransferases: when the start matters. Trends BiochemSci. 2012; 37:152-161. doi: 10.1016/j.tibs.2012.02.003 PMID: 22405572
88. Dyer RB, McMurray CT. Mutant protein in Huntington disease is resistant to proteolysis in affected brain. Nat Genet. 2001; 29:270-278. PMID: 11600884