α-Lactalbumin, Engineered to be Nonnative and Inactive, Kills Tumor Cells when in Complex with Oleic Acid: A New Biological Function Resulting from Partial Unfolding

Journal of Molecular Biology

Volumn 394, Issue 5, 2009, Pages 994-1010

  Pettersson Kastberg, Jenny ^a   Mossberg, Ann Kristin ^a   Trulsson, Maria ^a   Yong, Yeon Joong ^a,b   Min, Soyoung ^b   Lim, Yoongho ^c   O'Brien, John E ^b   Svanborg, Catharina ^a,d   Mok, K Hun ^a,b  

^a Faculty of Medicine   (Sweden)

^b TRINITY COLLEGE DUBLIN   (Ireland)

^c Konkuk University   (South Korea)

^d AGENCY FOR SCIENCE   (Singapore)

Author keywords

HAMLET; molten globule; partial unfolding; tumoricidal activity; lactalbumin

Indexed keywords

ALANINE; ALPHA LACTALBUMIN; CYSTEINE; OLEIC ACID;

AMINO ACID SUBSTITUTION; ANIMAL CELL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CELL MIGRATION; CELL NUCLEUS; CELL SURFACE; CONTROLLED STUDY; HUMAN; HUMAN CELL; LYMPHOMA CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN STRUCTURE; TUMOR CELL;

EID: 70450224072     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jmb.2009.09.026     Document Type: Article

References (89)

1. Permyakov E.A., and Berliner L.J. α-Lactalbumin: structure and function. FEBS Lett. 473 (2000) 269-274
2. Brodbeck U., Denton W.L., Tanahashi N., and Ebner K.E. The isolation and identification of the B protein of lactose synthetase as α-lactalbumin. J. Biol. Chem. 242 (1967) 1391-1397
3. Peng Z.-y., and Kim P.S. A protein dissection study of a molten globule. Biochemistry 33 (1994) 2136-2141
4. Kuwajima K. The molten globule state of α-lactalbumin. FASEB J. 10 (1996) 102-109
5. Ewbank J.J., Creighton T.E., Hayer-Hartl M.K., and Hartl F.-U. What is the molten globule?. Nat. Struct. Biol. 2 (1995) 10
6. Schulman B.A., Kim P.S., Dobson C.M., and Redfield C. A residue-specific NMR view of the non-cooperative unfolding of a molten globule. Nat. Struct. Biol. 4 (1997) 630-634
7. Chrysina E.D., Brew K., and Acharya K.R. Crystal structures of apo- and holo-bovine α-lactalbumin at 2.2-Å resolution reveal an effect of calcium on inter-lobe interactions. J. Biol. Chem. 275 (2000) 37021-37029
8. Mok K.H., Nagashima T., Day I.J., Hore P.J., and Dobson C.M. Multiple subsets of side-chain packing in partially folded states of α-lactalbumins. Proc. Natl. Acad. Sci. USA 102 (2005) 8899-8904
9. Arai M., and Kuwajima K. Role of the molten globule state in protein folding. Adv. Protein Chem. 53 (2000) 209-282
10. Ptitsyn O.B. Molten globule and protein folding. Adv. Protein Chem. 47 (1995) 83-229
11. Ren J., Stuart D.I., and Acharya K.R. α-Lactalbumin possesses a distinct zinc binding site. J. Biol. Chem. 268 (1993) 19292-19298
12. Wu L.C., Peng Z.-y., and Kim P.S. Bipartite structure of the α-lactalbumin molten globule. Nat. Struct. Biol. 2 (1995) 281-286
13. Peng Z.-y., Wu L.C., and Kim P.S. Local structural preferences in the α-lactalbumin molten globule. Biochemistry 34 (1995) 3248-3252
14. Wu L.C., Schulman B.A., Peng Z.-y., and Kim P.S. Disulfide determinants of calcium-induced packing in α-lactalbumin. Biochemistry 35 (1996) 859-863
15. Redfield C., Schulman B.A., Milhollen M.A., Kim P.S., and Dobson C.M. α-Lactalbumin forms a compact molten globule in the absence of disulfide bonds. Nat. Struct. Biol. 6 (1999) 948-952
16. Vendruscolo M., Paci E., Karplus M., and Dobson C.M. Structures and relative free energies of partially folded states of proteins. Proc. Natl Acad. Sci. USA 100 (2003) 14817-14821
17. Saeki K., Arai M., Yoda T., Nakao M., and Kuwajima K. Localized nature of the transition-state structure in goat α-lactalbumin folding. J. Mol. Biol. 341 (2004) 589-604
18. Håkansson A., Zhivotovsky B., Orrenius S., Sabharwal H., and Svanborg C. Apoptosis induced by a human milk protein. Proc. Natl. Acad. Sci. USA 92 (1995) 8064-8068
19. Svensson M., Sabharwal H., Håkansson A., Mossberg A.-K., Lipiunas P., Leffler H., et al. Molecular characterization of α-lactalbumin folding variants that induce apoptosis in tumor cells. J. Biol. Chem. 274 (1999) 6388-6396
20. Svensson M., Håkansson A., Mossberg A.-K., Linse S., and Svanborg C. Conversion of α-lactalbumin to a protein inducing apoptosis. Proc. Natl. Acad. Sci. USA 97 (2000) 4221-4226
21. Pettersson J., Mossberg A.-K., and Svanborg C. α-Lactalbumin species variation, HAMLET formation, and tumor cell death. Biochem. Biophys. Res. Commun. 345 (2006) 260-270
22. Breckenridge W.C., and Kuksis A. Molecular weight distributions of milk fat triglycerides from seven species. J. Lipid Res. 8 (1967) 473-478
23. Hamosh M., Bitman J., Wood L., Hamosh P., and Mehta N.R. Lipids in milk and the first steps in their digestion. Pediatrics 75 (1985) 146-150
24. Heine W.E., Klein P.D., and Reeds P.J. The importance of α-lactalbumin in infant nutrition. J. Nutr. 121 (1991) 277-283
25. Lonnerdal B., and Forsum E. Casein content of human milk. Am. J. Clin. Nutr. 41 (1985) 113-120
26. Svanborg C., Ågerstam H., Aronsson A., Bjerkvig R., Düringer C., Fischer W., et al. HAMLET kills tumor cells by an apoptosis-like mechanism-cellular, molecular, and therapeutic aspects. Adv. Cancer Res. 88 (2003) 1-29
27. Mok K.H., Pettersson J., Orrenius S., and Svanborg C. Mini review: HAMLET, protein folding, and tumor cell death. Biochem. Biophys. Res. Commun. 354 (2007) 1-7
28. Gustafsson L., Leijonhufvud I., Aronsson A., Mossberg A.-K., and Svanborg C. Treatment of skin papillomas with topical α-lactalbumin-oleic acid. N. Engl. J. Med. 350 (2004) 2663-2672
29. Mossberg A.-K., Wullt B., Gustafsson L., Månsson W., Ljunggren E., and Svanborg C. Bladder cancers respond to intravesical instillation of HAMLET (human α-lactalbumin made lethal to tumor cells). Int. J. Cancer 121 (2007) 1352-1359
30. Fischer W., Gustafsson L., Mossberg A.-K., Gronli J., Mork S., Bjerkvig R., and Svanborg C. Human α-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res. 64 (2004) 2105-2112
31. Svensson M., Fast J., Mossberg A.-K., Düringer C., Gustafsson L., Hallgren O., et al. α-Lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human a-lactalbumin made lethal to tumor cells). Protein Sci. 12 (2003) 2794-2804
32. Svensson M., Mossberg A.-K., Pettersson J., Linse S., and Svanborg C. Lipids as cofactors in protein folding: Stereo-specific lipid-protein interactions are required to form HAMLET (human α-lactalbumin made lethal to tumor cells). Protein Sci. 12 (2003) 2805-2814
33. Casbarra A., Birolo L., Infusini G., Dal Piaz F., Svensson M., Pucci P., et al. Conformational analysis of HAMLET, the folding variant of human α-lactalbumin associated with apoptosis. Protein Sci. 13 (2004) 1322-1330
34. Fast J., Mossberg A.-K., Svanborg C., and Linse S. Stability of HAMLET-a kinetically trapped α-lactalbumin oleic acid complex. Protein Sci. 14 (2005) 329-340
35. Halskau Ø., Underhaug J., Frøystein N.Å., and Martínez A. Conformational flexibility of α-lactalbumin related to its membrane binding capacity. J. Mol. Biol. 349 (2005) 1072-1086
36. Permyakov S.E., Pershikova I.V., Zhadan A.P., Goers J., Bakunts A.G., Uversky V.N., et al. Conversion of human α-lactalbumin to an apo-like state in the complexes with basic poly-amino acids: towards understanding of the molecular mechanism of antitumor action of HAMLET. J. Proteome Res. 4 (2005) 564-569
37. Knyazeva E.L., Grishchenko V.M., Fadeev R.S., Akatov V.S., Permyakov S.E., and Permyakov E.A. Who is Mr. HAMLET? Interaction of human α-lactalbumin with monomeric oleic acid. Biochemistry 47 (2008) 13127-13137
38. Bemporad F., Gsponer J., Hopearuoho H.I., Plakoutsi G., Stati G., Stefani M., et al. Biololgical function in a non-native partially folded state of a protein. EMBO J. 27 (2008) 1525-1535
39. Fink A.L. Natively unfolded proteins. Curr. Opin. Struct. Biol. 15 (2005) 35-41
40. Pettersson-Kastberg J., Aits S., Gustafsson L., Mossberg A.-K., Storm P., Trulsson M., et al. Can misfolded proteins be beneficial? The HAMLET case (Review). Ann. Med. 41 (2009) 162-176
41. Koradi R., Billeter M., and Wüthrich K. MOLMOL: a program for display and analysis of macromolecular structures. J. Mol. Graph. 14 (1996) 51-55
42. Kamijima T., Ohmura A., Sato T., Akimoto K., Itabashi M., Mizuguchi M., et al. Heat-treatment method for producing fatty acid-bound α-lactalbumin that induces tumor cell death. Biochem. Biophys. Res. Commun. 376 (2008) 211-214
43. Dolgikh D.A., Gilmanshin R.I., Brazhnikov E.V., Bychkova V.E., Semisotnov G.V., Venyaminov S.Y., and Ptitsyn O.B. α-Lactalbumin: compact state with fluctuating tertiary structure?. FEBS Lett. 136 (1981) 311-315
44. Turner D.C., and Brand L. Quantitative estimation of protein binding site polarity. Fluorescence of N-arylaminonaphthalenesulfonates. Biochemistry 7 (1968) 3381-3390
45. Semisotnov G.V., Rodionova N.A., Razgulyaev O.I., Uversky V.N., Gripas A.F., and Gilmanshin R.I. Study of the "molten globule" intermediate state in protein folding by a hydrophobic fluorescent probe. Biopolymers 31 (1991) 119-128
46. Balbach J., Forge V., Lau W.S., Jones J.A., van Nuland N.A.J., and Dobson C.M. Detection of residue contacts in a protein folding intermediate. Proc. Natl. Acad. Sci. USA 94 (1997) 7182-7185
47. Wijesinha-Bettoni R., Dobson C.M., and Redfield C. Comparison of the structural and dynamical properties of holo and apo bovine α-lactalbumin by NMR spectroscopy. J. Mol. Biol. 307 (2001) 885-898
48. Ramboarina S., and Redfield C. Structural characterisation of the human α-lactalbumin molten globule at high temperature. J. Mol. Biol. 330 (2003) 1177-1188
49. Ramboarina S., and Redfield C. Probing the effect of temperature on the backbone dynamics of the human α-lactalbumin molten globule. J. Am. Chem. Soc. 130 (2008) 15318-15326
50. 1H NMR. Biochemistry 32 (1993) 13198-13203
51. Chiti F., and Dobson C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75 (2006) 333-366
52. Goers J., Permyakov S.E., Permyakov E.A., Uversky V.N., and Fink A.L. Conformational prerequisites for α-lactalbumin fibrillation. Biochemistry 41 (2002) 12456-12551
53. Düringer C., Hamiche A., Gustafsson L., Kimura H., and Svanborg C. HAMLET interacts with histones and chromatin in tumor cell nuclei. J. Biol. Chem. 278 (2003) 42131-42135
54. Gavrieli Y., Sherman Y., and Ben-Sasson S.A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119 (1992) 493-501
55. Anfinsen C.B. Principles that govern the folding of protein chains. Science 181 (1973) 223-230
56. Fowler D.M., Koulov A.V., Alory-Jost C., Marks M.S., Balch W.E., and Kelly J.W. Functional amyloid formation within mammalian tissue. PLoS Biol. 4 (2006) e6
57. Huff M.E., Balch W.E., and Kelly J.W. Pathological and functional amyloid formation orchestrated by the secretory pathway. Curr. Opin. Struct. Biol. 13 (2003) 674-682
58. Tessier P.M., and Lindquist S. Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 447 (2007) 556-561
59. Shorter J., and Lindquist S. Prions as adaptive conduits of memory and inheritance. Nat. Rev. Genet. 6 (2005) 435-450
60. Acharya K.R., Ren J., Stuart D.I., Phillips D.C., and Fenna R.E. Crystal structure of human α-lactalbumin at 1.7 Å resolution. J. Mol. Biol. 221 (1991) 571-581
61. Anderson P.J., Brooks C.L., and Berliner L.J. Functional identification of calcium binding residues in bovine α-lactalbumin. Biochemistry 36 (1997) 11648-11654
62. Wijesinha-Bettoni R., Dobson C.M., and Redfield C. Comparison of the denaturant-induced unfolding of the bovine and human α-lactalbumin molten globules. J. Mol. Biol. 312 (2001) 261-273
63. Last A.M., Schulman B.A., Robinson C.V., and Redfield C. Probing subtle differences in the hydrogen exchange behavior of variants of the human α-lactalbumin molten globule using mass spectrometry. J. Mol. Biol. 311 (2001) 909-919
64. Lassalle M.W., Li H., Yamada H., Akasaka K., and Redfield C. Pressure-induced unfolding of the molten globule of all-Ala α-lactalbumin. Protein Sci. 12 (2003) 66-72
65. Quezada C.M., Schulman B.A., Froggatt J.J., Dobson C.M., and Redfield C. Local and global cooperativity in the human α-lactalbumin molten globule. J. Mol. Biol. 338 (2004) 149-158
66. Kim S., Bracken C., and Baum J. Characterization of millisecond time-scale dynamics in the molten globule state of α-lactalbumin by NMR. J. Mol. Biol. 294 (1999) 551-560
67. Eliezer D., Yao J., Dyson H.J., and Wright P.E. Structural and dynamic characterization of partially folded states of apomyoglobin and implications for protein folding. Nat. Struct. Biol. 5 (1998) 148-155
68. Eliezer D., Chung J., Dyson H.J., and Wright P.E. Native and non-native secondary structure and dynamics in the pH 4 intermediate of apomyoglobin. Biochemistry 39 (2000) 2894-2901
69. Eliezer D., Jennings P.A., Dyson H.J., and Wright P.E. Populating the equilibrium molten globule state of apomyoglobin under conditions suitable for structural characterization by NMR. FEBS Lett. 417 (1997) 92-96
70. Smith L.J., Dobson C.M., and van Gunsteren W.F. Side-chain conformational disorder in a molten globule: molecular dynamic simulations of the A-state of human α-lactalbumin. J. Mol. Biol. 286 (1999) 1567-1580
71. Paci E., Smith L.J., Dobson C.M., and Karplus M. Exploration of partially unfolded states of human α-lactalbumin by molecular dynamics simulation. J. Mol. Biol. 306 (2001) 329-347
72. Schmid N., Bolliger C., Smith L.J., and van Gunsteren W.F. Disulfide bond shuffling in bovine α-lactalbumin: MD simulation confirms experiment. Biochemistry 47 (2008) 12104-12107
73. Halskau Jr. Ø., Perez-Jimenez R., Ibarra-Molero B., Underhaug J., Muñoz V., Martínez A., and Sanchez-Ruiz J.M. Large-scale modulation of thermodynamic protein folding barriers linked to electrostatics. Proc. Natl. Acad. Sci. USA 105 (2008) 8625-8630
74. Gharibyan A.L., Zamotin V., Yanamandra K., Moskaleva O.S., Margulis B.A., Kostanyan I.A., and Morozova-Roche L.A. Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways. J. Mol. Biol. 365 (2007) 1337-1349
75. Jeffery C.J. Moonlighting protein: old proteins learning new tricks. Trends Genet. 19 (2003) 415-417
76. Tompa P., Szász C., and Buday L. Structural disorder throws new light on moonlighting. Trends Biochem. Sci. 30 (2005) 484-489
77. Lindahl L., and Vogel H.J. Metal-ion-dependent hydrophobic-interaction chromatography of α-lactalbumins. Anal. Biochem. 140 (1984) 394-402
78. Schulman B.A., Redfield C., Peng Z.-y., Dobson C.M., and Kim P.S. Different subdomains are most protected from hydrogen exchange in the molten globule and native states of human α-lactalbumin. J. Mol. Biol. 253 (1995) 651-657
79. Grobler J.A., Wang M., Pike A.C.W., and Brew K. Study by mutagenesis of the roles of two aromatic clusters of α-lactalbumin in aspects of its action in the lactose synthase system. J. Biol. Chem. 269 (1994) 5106-5114
80. Ishikawa N., Chiba T., Chen L.T., Shimizu A., Ikeguchi M., and Sugai S. Remarkable destabilization of recombinant α-lactalbumin by an extraneous N-terminal methionyl residue. Protein Eng. 11 (1998) 333-335
81. Chaudhuri T.K., Horii K., Yoda T., Arai M., Nagata S., Terada T.P., et al. Effect of the extra N-terminal methionine residue on the stability and folding of recombinant α-lactalbumin expressed in Escherichia coli. J. Mol. Biol. 285 (1999) 1179-1194
82. Greene L.H., Grobler J.A., Malinovskii V.A., Tian J., Acharya K.R., and Brew K. Stability, activity and flexibility in α-lactalbumin. Protein Eng. 12 (1999) 581-587
83. Permyakov S.E., Uversky V.N., Veprintsev D.B., Cherskaya A.M., Brooks C.L., Permyakov E.A., and Berliner L.J. Mutating aspartate in the calcium-binding site of α-lactalbumin: effects on the protein stability and cation binding. Protein Eng. 14 (2001) 785-789
84. Nozaka M., Kuwajima K., Nitta K., and Sugai S. Detection and characterization of the intermediate on the folding pathway of human α-lactalbumin. Biochemistry 17 (1978) 3753-3758
85. 1H NMR studies of molten globule proteins in aqueous media. J. Biomol. NMR 4 (1994) 859-862
86. De Marco A. pH dependence of internal references. J. Magn. Reson. 26 (1977) 527-528
87. Dehner A., and Kessler H. Diffusion NMR spectroscopy: folding and aggregation of domains in p53. ChemBioChem 6 (2005) 1550-1565
88. Baldwin A.J., Anthony-Cahill S.J., Knowles T.P., Lippens G., Christodoulou J., Barker P.D., and Dobson C.M. Measurement of amyloid fibril length distributions by inclusion of rotational motion in solution NMR diffusion measurements. Angew. Chem., Int. Ed. Engl. 47 (2008) 3385-3387
89. Wilkins D.K., Grimshaw S.B., Receveur V., Dobson C.M., Jones J.A., and Smith L.J. Hydrodynamic radii of native and denatured proteins measured by pulse field gradient NMR techniques. Biochemistry 38 (1999) 16424-16431