The Protein Journal

, Volume 36, Issue 5, pp 385–396 | Cite as

Sequence, Structural Analysis and Metrics to Define the Unique Dynamic Features of the Flap Regions Among Aspartic Proteases

  • Lara McGillewie
  • Muthusamy Ramesh
  • Mahmoud E. Soliman
Article

Abstract

Aspartic proteases are a class of hydrolytic enzymes that have been implicated in a number of diseases such as HIV, malaria, cancer and Alzheimer’s. The flap region of aspartic proteases is a characteristic unique structural feature of these enzymes; and found to have a profound impact on protein overall structure, function and dynamics. Flap dynamics also plays a crucial role in drug binding and drug resistance. Therefore, understanding the structure and dynamic behavior of this flap regions is crucial in the design of potent and selective inhibitors against aspartic proteases. Defining metrics that can describe the flap motion/dynamics has been a challenging topic in literature. This review is the first attempt to compile comprehensive information on sequence, structure, motion and metrics used to assess the dynamics of the flap region of different aspartic proteases in “one pot”. We believe that this review would be of critical importance to the researchers from different scientific domains.

Keywords

Flap dynamics Protein flexibility Aspartic proteases Hydrolytic enzymes 

Notes

Acknowledgements

The authors would like to acknowledge the National Research Foundation (NRF), South Africa and School of Health Science, University of KwaZulu-Natal, Westville, Durban, South Africa for the financial assistance.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflict of interest.

References

  1. 1.
    Boehr DD, Dyson HJ, Wright PE (2006) An NMR perspective on enzyme dynamics. Chem Rev 106:3055–3079CrossRefGoogle Scholar
  2. 2.
    Cooper JB (2002) Aspartic proteinases in disease: a structural perspective. Curr Drug Targets 3:155–173CrossRefGoogle Scholar
  3. 3.
    Dunn BM (2002) Structure and mechanism of the pepsin-like family of aspartic peptidases. Chem Rev 102:4431–4458CrossRefGoogle Scholar
  4. 4.
    Northrop DB (2001) Follow the protons: a low-barrier hydrogen bond unifies the mechanisms of the aspartic proteases. Acc Chem Res 34:790–797CrossRefGoogle Scholar
  5. 5.
    Davies D (1990) The structure and function of the aspartic proteinases. Annu Rev Biophys Biomol Struct 19:189–215CrossRefGoogle Scholar
  6. 6.
    Simões I, Faro C (2004) Structure and function of plant aspartic proteinases. Eur J Biochem 271:2067–2075CrossRefGoogle Scholar
  7. 7.
    Castro HC, Abreu PA, Geraldo RB, Martins RCA, dos Santos R, Loureiro NIV, Cabral LM, Rodrigues CR (2011) Looking at the proteases from a simple perspective. J Mol Recognit 24:165–181CrossRefGoogle Scholar
  8. 8.
    Tang J, James MNG, Hsu IN, Jenkins JA, Blundell TL (1978) Structural evidence for gene duplication in the evolution of the acid proteases. Nature 271:618–621CrossRefGoogle Scholar
  9. 9.
    Swanstrom R (2000) Human immunodeficiency virus type-1 protease inhibitors therapeutic successes and failures, suppression and resistance. Pharmacol Ther 86:145–170CrossRefGoogle Scholar
  10. 10.
    Sharma SK, Evans DB, Hui JO, Heinrikson RL (1991) Could angiotensin I be produced from a renin substrate by the HIV-1 protease? Anal Biochem 198:363–367CrossRefGoogle Scholar
  11. 11.
    Rawlings ND, Barrett AJ (1995) Familes of aspartic peptidases, and those of unknown catalytic mechanism. Methods 248:1995Google Scholar
  12. 12.
    Cascella M, Micheletti C, Rothlisberger U, Carloni P (2005) Evolutionary conserved functional mechanics across pepsin-like and retroviral aspartic proteases. J Am Chem Soc 127:3734–3742CrossRefGoogle Scholar
  13. 13.
    Sielecki AR, Fujinaga M, Read RJ, James MNG (1991) Refined structure of porcine pepsinogen at 1·8 Å resolution. J Mol Biol 219:671–692CrossRefGoogle Scholar
  14. 14.
    Hong L, Tang J (2004) Flap position of free memapsin 2 (β-Secretase), a model for flap opening in aspartic protease catalysis. BioChemistry 43:4689–4695CrossRefGoogle Scholar
  15. 15.
    Patel S, Vuillard L, Cleasby A, Murray CW, Yon J (2004) Apo and inhibitor complex structures of BACE (β-secretase). J Mol Biol 343:407–416CrossRefGoogle Scholar
  16. 16.
    Tóth G, Borics A (2006) Closing of the flaps of HIV-1 protease induced by substrate binding: a model of a flap closing mechanism in retroviral aspartic proteases. Biochemistry 45:6606–6614CrossRefGoogle Scholar
  17. 17.
    Barman A, Prabhakar R (2014) Computational insights into substrate and site specificities, catalytic mechanism, and protonation states of the catalytic Asp Dyad of β -secretase. Scientifica 2014:598728CrossRefGoogle Scholar
  18. 18.
    Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon AR, Scolnick EM, Sigal IS (1988) Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci USA 85:4686–4690CrossRefGoogle Scholar
  19. 19.
    Seelmeier S, Schmidt H, Turk V, von der Helm K (1988) Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc Natl Acad Sci USA 85:6612–6616CrossRefGoogle Scholar
  20. 20.
    Katz R (1994) The retroviral enzymes. Annu Rev Biochem 63:133–173CrossRefGoogle Scholar
  21. 21.
    Czodrowski P, Sotriffer CA, Klebe G (2007) Atypical protonation states in the active site of hiv-1 protease: a computational study. J Chem Inf Model 47:1590–1598CrossRefGoogle Scholar
  22. 22.
    Scott WR, Schiffer CA (2000) Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance. Structure 8:1259–1265CrossRefGoogle Scholar
  23. 23.
    Hornak V, Okur A, Rizzo RC, Simmerling C (2006) HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations. Proc Natl Acad Sci USA 103:915–920CrossRefGoogle Scholar
  24. 24.
    Hornak V, Simmerling C (2007) Targeting structural flexibility in HIV-1 protease inhibitor binding. Drug Discov Today 12:132–138CrossRefGoogle Scholar
  25. 25.
    Spinelli S, Liu Q, Alzari P, Poljak R (1991) The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie 73:1391–1396CrossRefGoogle Scholar
  26. 26.
    Lapatto R, Blundell T, Hemmings A, Overington J, Wilderspin A, Wood S, Merson JR, Whittle PJ, Danley DE, Geoghegan KF, Hawrylik SJ, Lee SE, Scheld KG, Hobart PM (1989) X-ray analysis of HIV-1 proteinase at 2.7 Å resolution confirms structural homology among retroviral enzymes. Nature 342:299–302CrossRefGoogle Scholar
  27. 27.
    Wlodawer A, Miller M, Jaskolski M, Sathyanarayana BL, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245:616–621CrossRefGoogle Scholar
  28. 28.
    Ishima R, Freedberg DI, Wang YX, Louis JM, Torchia DA (1999) Flap opening and dimer-interface flexibility in the free and inhibitor-bound HIV protease, and their implications for function. Structure 7:1047–1055CrossRefGoogle Scholar
  29. 29.
    Freedberg DI, Ishima R, Jacob J, Wang YX, Kustanovich I, Louis JM, Torchia DA (2009) Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations. Protein Sci 11:221–232CrossRefGoogle Scholar
  30. 30.
    Katoh E, Louis JM, Yamazaki T, Gronenborn AM, Torchia DA, Ishima R (2003) A solution NMR study of the binding kinetics and the internal dynamics of an HIV-1 protease-substrate complex. Protein Sci 12:1376–1385CrossRefGoogle Scholar
  31. 31.
    Nicholson LK, Yamazaki T, Torchia DA, Grzesiek S, Bax A, Stahl SJ, Kaufman JD, Wingfield PT, Lam PY, Jadhav PK, Hodge CN, Domaille PJ, Chang CH (1995) Flexibility and function in HIV-1 protease. Nat Struct Biol 2:274–280CrossRefGoogle Scholar
  32. 32.
    Wu X, Öhrngren P, Ekegren JK, Unge J, Unge T, Wallberg H, Samuelsson B, Hallberg A, Larhed M (2008) Two-carbon-elongated hiv-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic. J Med Chem 51:1053–1057CrossRefGoogle Scholar
  33. 33.
    Clavel F, Hance AJ (2004) HIV drug resistance. N Engl J Med 350:1023–1035CrossRefGoogle Scholar
  34. 34.
    Velazquez-Campoy A, Muzammil S, Ohtaka H, Schon A, Vega S, Freire E (2003) Structural and thermodynamic basis of resistance to hiv-1 protease inhibition: implications for inhibitor design. Curr Drug Target Infect Disord 3:311–328CrossRefGoogle Scholar
  35. 35.
    Muzammil S, Ross P, Freire E (2003) A major role for a set of non-active site mutations in the development of hiv-1 protease drug resistance. Biochemistry 42:631–638CrossRefGoogle Scholar
  36. 36.
    Dam E, Quercia R, Glass B, Descamps D, Launay O, Duval X, Kräusslich HG, Hance AJ, Clavel F (2009) Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog 5:e1000345CrossRefGoogle Scholar
  37. 37.
    Ohtaka H, Schön A, Freire E (2003) Multidrug resistance to hiv-1 protease inhibition requires cooperative coupling between distal mutations. Biochemistry 42:13659–13666CrossRefGoogle Scholar
  38. 38.
    Ahmed SM, Maguire, GEM, Kruger HG, Govender T (2014) The impact of active site mutations of South African HIV PR on drug resistance: insight from molecular dynamics simulations, binding free energy and per-residue footprints. Chem Biol Drug Des 83:472–481CrossRefGoogle Scholar
  39. 39.
    Tóth G, Borics A (2006) Flap opening mechanism of HIV-1 protease. J Mol Graph Model 24:465–474CrossRefGoogle Scholar
  40. 40.
    Zhu ZW, Schuster DI, Tuckerman ME (2003) Molecular dynamics study of the connection between flap closing and binding of fullerene-based inhibitors of the HIV-1 protease. Biochemistry 42:1326–1333CrossRefGoogle Scholar
  41. 41.
    Heaslet H, Rosenfeld R, Giffin M, Lin YC, Tam K, Torbett BE, Elder JH, McRee DE, Stout CD (2007) Conformational flexibility in the flap domains of ligand-free HIV protease. Acta Crystallogr Sect D 63:866–875CrossRefGoogle Scholar
  42. 42.
    Torbeev VY, Raghuraman H, Mandal K, Senapati S, Perozo E, Kent SBH (2009) Dynamics of “flap” structures in three hiv-1 protease/inhibitor complexes probed by total chemical synthesis and pulse-epr spectroscopy. J Am Chem Soc 131:884–885CrossRefGoogle Scholar
  43. 43.
    Galiano L, Bonora M, Fanucci GE (2007) Interflap distances in HIV-1 protease determined by pulsed EPR measurements. J Am Chem Soc 129:11004–11005CrossRefGoogle Scholar
  44. 44.
    Karthik S, Senapati S (2011) Dynamic flaps in HIV-1 protease adopt unique ordering at different stages in the catalytic cycle. Proteins Struct Funct Bioinform 79:1830–1840CrossRefGoogle Scholar
  45. 45.
    Meher BR, Wang Y (2012) Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free energy studies. J Phys Chem B 116:1884–1900CrossRefGoogle Scholar
  46. 46.
    Seibold SA, Cukier RI (2007) A molecular dynamics study comparing a wild-type with a multiple drug resistant HIV protease: differences in flap and aspartate 25 cavity dimensions. Proteins Struct Funct Bioinform 69:551–565CrossRefGoogle Scholar
  47. 47.
    Chibi B (2012) Computational studies of pentacycloundecane peptide based HIV-1 protease inhibitors. University of KwaZulu-Natal, Durban (A project report)Google Scholar
  48. 48.
    WHO—World Health Organization (2015)Google Scholar
  49. 49.
    Ersmark K, Samuelsson B, Hallberg A (2006) Plasmepsins as potential targets for new antimalarial therapy. Med Res Rev 26:626–666CrossRefGoogle Scholar
  50. 50.
    White NJ (1993) Malaria parasites go ape. Lancet 341:793CrossRefGoogle Scholar
  51. 51.
    Banerjee R, Liu J, Beatty W, Pelosof L, Klemba M, Goldberg DE (2002) Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc Natl Acad Sci USA 99:990–995CrossRefGoogle Scholar
  52. 52.
    Rosenthal PJ (1998) Proteases of malaria parasites: new targets for chemotherapy. Emerg Infect Dis 4:49–57CrossRefGoogle Scholar
  53. 53.
    Coombs GH, Goldberg DE, Klemba M, Berry C, Kay J, Mottram JC (2001) Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol 17:532–537CrossRefGoogle Scholar
  54. 54.
    Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan M, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498–511CrossRefGoogle Scholar
  55. 55.
    Goldberg DE (1993) Hemoglobin degradation in Plasmodium-infected red blood cells. Semin Cell Biol 4:355–361CrossRefGoogle Scholar
  56. 56.
    Francis SE, Sullivan DJ Jr, Goldberg DE (1997) Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu Rev Microbiol 51:97–123CrossRefGoogle Scholar
  57. 57.
    Sherman IW (1977) Amino acid metabolism and protein synthesis in malarial parasites. Bull World Heal Organ 55:265–276Google Scholar
  58. 58.
    Gluzman IY, Francis SE, Oksman A, Smith CE, Duffin KL, Goldberg DE (1994) Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway. J Clin Invest 93:1602–1608CrossRefGoogle Scholar
  59. 59.
    Liu J, Istvan ES, Gluzman IY, Gross J, Goldberg DE (2006) Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems. Proc Natl Acad Sci USA 103:8840–8845CrossRefGoogle Scholar
  60. 60.
    Dame JB, Yowell C, Omara-Opyene L, Carlton JM, Cooper R, Li T (2003) Plasmepsin 4, the food vacuole aspartic proteinase found in all Plasmodium spp. infecting man. Mol Biochem Parasitol 130:1–12CrossRefGoogle Scholar
  61. 61.
    Omara-Opyene AL, Moura PA, Sulsona CR, Bonilla JA, Yowell CA, Fujioka H, Fidock DA, Dame JB (2004) Genetic disruption of the Plasmodium falciparum digestive vacuole plasmepsins demonstrates their functional redundancy. J Biol Chem 279:54088–54096CrossRefGoogle Scholar
  62. 62.
    Klemba M, Goldberg DE (2005) Characterization of plasmepsin V, a membrane-bound aspartic protease homolog in the endoplasmic reticulum of Plasmodium falciparum. Mol Biochem Parasitol 143:183–191CrossRefGoogle Scholar
  63. 63.
    Boddey JA, Hodder AN, Gunther S, Gilson PR, Patsiouras H, Kapp EA, Pearce JA, de Koning-Ward TF, Simpson RJ, Crabb BS, Cowman AF (2010) An aspartyl protease directs malaria effector proteins to the host cell. Nature 463:627–631CrossRefGoogle Scholar
  64. 64.
    Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE (2010) Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte. Nature 463:632–636CrossRefGoogle Scholar
  65. 65.
    Hodder AN, Sleebs BE, Czabotar PE, Gazdik M, Xu Y, O’Neill MT, Lopaticki S, Nebl T, Triglia T, Smith BJ, Lowes K, Boddey JA, Cowman AF (2015) Structural basis for plasmepsin V inhibition that blocks export of malaria proteins to human erythrocytes. Nat Struct Mol Biol 22:590–596CrossRefGoogle Scholar
  66. 66.
    Marti M, Good RT, Rug M, Knuepfer E, Cowman AF (2004) Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306:1930–1933CrossRefGoogle Scholar
  67. 67.
    Hiller NL, Bhattacharjee S, van Ooij C, Liolios K, Harrison T, Lopez-Estrano C, Haldar K (2004) A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306:1934–1937CrossRefGoogle Scholar
  68. 68.
    Asojo OA, Gulnik SV, Afonina E, Yu B, Ellman JA, Haque TS, Silva AM (2003) Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum. J Mol Biol 327:173–181CrossRefGoogle Scholar
  69. 69.
    Karubiu W, Bhakat S, McGillewie L, Soliman ME (2015) Flap dynamics of plasmepsin proteases: insight into proposed parameters and molecular dynamics. Mol Biosyst 11:1061–1066CrossRefGoogle Scholar
  70. 70.
    Asojo OA, Afonina E, Gulnik SV, Yu B, Erickson JW, Randad R, Medjahed D, Silva AM (2002) Structures of Ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 Å in complex with the inhibitors rs367 and rs370. Acta Crystallogr Sect D 58:2001–2008CrossRefGoogle Scholar
  71. 71.
    Bhaumik P, Horimoto Y, Xiao H, Miura T, Hidaka K, Kiso Y, Wlodawer A, Yada RY, Gustchina A (2011) Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum. J Struct Biol 175:73–84CrossRefGoogle Scholar
  72. 72.
    Westling J, Cipullo P, Hung SH, Saft H, Dame JB, Dunn BM (1999) Active site specificity of plasmepsin II. Protein Sci 8:2001–2009CrossRefGoogle Scholar
  73. 73.
    McGillewie L, Soliman ME (2015) Flap flexibility amongst plasmepsins I, II, III, IV, and V: sequence, structural, and molecular dynamics analyses. Proteins Struct Funct Bioinform 83:1693–1705CrossRefGoogle Scholar
  74. 74.
    Tice CM (2006) Renin inhibitors. Annu Rep Med Chem 41:155–167CrossRefGoogle Scholar
  75. 75.
    Paul M (2006) Physiology of local renin-angiotensin systems. Physiol Rev 86:747–803CrossRefGoogle Scholar
  76. 76.
    Wood JM, Stanton JL, Hofbauer KG (1987) Inhibitors of renin as potential therapeutic agents. J Enzym Inhib 1:169–185CrossRefGoogle Scholar
  77. 77.
    Powell NA, Ciske FL, Cai C, Holsworth DD, Mennen K, Van Huis CA, Jalaie M, Day J, Mastronardi M, McConnell P (2007) Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors. Bioorg Med Chem 15:5912–5949CrossRefGoogle Scholar
  78. 78.
    Hedner T, Sun X, Junggren IL, Pettersson A, Edvinsson L (1992) Peptides as targets for antihypertensive drug development. J Hypertens Suppl 10:S121–S132CrossRefGoogle Scholar
  79. 79.
    Cody RJ (1994) The clinical potential of renin inhibitors and angiotensin antagonists. Drugs 47:586–598CrossRefGoogle Scholar
  80. 80.
    Staessen JA, Li Y, Richart T (2006) Oral renin inhibitors. Lancet 368:1449–1456CrossRefGoogle Scholar
  81. 81.
    Fisher NDL, Hollenberg NK (2005) Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol 16:592–599CrossRefGoogle Scholar
  82. 82.
    Azizi M, Webb R, Nussberger J, Hollenberg NK (2006) Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 24:243–256CrossRefGoogle Scholar
  83. 83.
    Brown MJ (2008) Aliskiren. Circulation 118:773–784CrossRefGoogle Scholar
  84. 84.
    Tzoupis H, Leonis G, Megariotis G, Supuran CT, Mavromoustakos T, Papadopoulos MG (2012) Dual inhibitors for aspartic proteases HIV-1 PR and renin: advancements in AIDS–hypertension–diabetes linkage via molecular dynamics, inhibition assays, and binding free energy calculations. J Med Chem 55:5784–5796CrossRefGoogle Scholar
  85. 85.
    Scheiper B, Matter H, Steinhagen H, Stilz U, Böcskei Z, Fleury V, McCort G (2010) Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors. Bioorg Med Chem Lett 20:6268–6272CrossRefGoogle Scholar
  86. 86.
    Politi A, Leonis G, Tzoupis H, Ntountaniotis D, Papadopoulos MG, Grdadolnik SG, Mavromoustakos T (2011) Conformational properties and energetic analysis of aliskiren in solution and receptor site. Mol Inform 30:973–985CrossRefGoogle Scholar
  87. 87.
    Rahuel J, Priestle JP, Grütter MG (1991) The crystal structures of recombinant glycosylated human renin alone and in complex with a transition state analog inhibitor. J Struct Biol 107:227–236CrossRefGoogle Scholar
  88. 88.
    Rahuel J, Rasetti V, Maibaum J, Rüeger H, Göschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood J, Grütter M (2000) Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol 7:493–504CrossRefGoogle Scholar
  89. 89.
    Baldwin ET, Bhat TN, Gulnik S, Hosur MV, Sowder RC, Cachau RE, Collins J, Silva AM, Erickson JW (1993) Crystal structures of native and inhibited forms of human cathepsin D: implications for lysosomal targeting and drug design. Proc Natl Acad Sci USA 90:6796–6800CrossRefGoogle Scholar
  90. 90.
    Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prébois C, Rochefort H, Vignon F (2006) Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett 237:167–179CrossRefGoogle Scholar
  91. 91.
    De Duve C (1983) Lysosomes revisited. Eur J Biochem 137:391–397CrossRefGoogle Scholar
  92. 92.
    Garcia M, Derocq D, Pujol P, Rochefort H (1990) Overexpression of transfected cathepsin D in transformed cells increases their malignant phenotype and metastatic potency. Oncogene 5:1809–1814Google Scholar
  93. 93.
    Liaudet E, Garcia M, Rochefort H (1994) Cathepsin D maturation and its stimulatory effect on metastasis are prevented by addition of KDEL retention signal. Oncogene 9:1145–1154Google Scholar
  94. 94.
    Liaudet E, Derocq D, Rochefort H, Garcia M (1995) Transfected cathepsin D stimulates high density cancer cell growth by inactivating secreted growth inhibitors. Cell Growth Differ 6:1045–1052Google Scholar
  95. 95.
    Glondu M, Coopman P, Laurent-Matha V, Garcia M, Rochefort H, Liaudet-Coopman E (2001) A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells. Oncogene 20:6920–6929CrossRefGoogle Scholar
  96. 96.
    Thies W, Bleiler L (2013) 2013 Alzheimer’s disease facts and figures. Alzheimers Dement 9:208–245CrossRefGoogle Scholar
  97. 97.
    Suo Z, Humphrey J, Kundtz A, Sethi F, Placzek A, Crawford F, Mullan M (1998) Soluble Alzheimers beta-amyloid constricts the cerebral vasculature in vivo. Neurosci Lett 257:77–80CrossRefGoogle Scholar
  98. 98.
    Pillot T, Drouet B, Queillé S, Labeur C, Vandekerckhove J, Rosseneu M, Pinçon-Raymond M, Chambaz J (1999) The nonfibrillar amyloid β-peptide induces apoptotic neuronal cell death: Involvement of its C-terminal fusogenic domain. J Neurochem 73:1626–1634CrossRefGoogle Scholar
  99. 99.
    Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741CrossRefGoogle Scholar
  100. 100.
    Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4:233–234CrossRefGoogle Scholar
  101. 101.
    Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V (1999) Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402:537–540CrossRefGoogle Scholar
  102. 102.
    Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi AL, Heinrikson RL, Gurney ME (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402:533–537CrossRefGoogle Scholar
  103. 103.
    Zhang Y, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3CrossRefGoogle Scholar
  104. 104.
    Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s β-secretase, have normal phenotype and abolished β-amyloid generation. Nat Neurosci 4:231–232CrossRefGoogle Scholar
  105. 105.
    Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R (2000) Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem 275:20647–20651CrossRefGoogle Scholar
  106. 106.
    Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, Song W (2005) Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J 19:739–749CrossRefGoogle Scholar
  107. 107.
    Yan R, Munzner JB, Shuck ME, Bienkowski MJ (2001) BACE2 Functions as an alternative alpha-secretase in cells. J Biol Chem 276:34019–34027CrossRefGoogle Scholar
  108. 108.
    Ahmed RR, Holler CJ, Webb RL, Li F, Beckett TL, Murphy MP (2010) BACE1 and BACE2 enzymatic activities in Alzheimer’s disease. J Neurochem 112:1045–1053CrossRefGoogle Scholar
  109. 109.
    Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J (2000) Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA 97:1456–1460CrossRefGoogle Scholar
  110. 110.
    Hong L, Turner RT, Koelsch G, Shin D, Ghosh AK, Tang J (2002) Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3. Biochemistry 41:10963–10967CrossRefGoogle Scholar
  111. 111.
    Hong L, Tang J (2004) Flap position of free memapsin 2 (beta-secretase), a model for flap opening in aspartic protease catalysis. Biochemistry 43:4689–4695CrossRefGoogle Scholar
  112. 112.
    Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J (2000) Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 290:150–153CrossRefGoogle Scholar
  113. 113.
    Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N (2008) Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Mol Cell Biol 28:3663–3671CrossRefGoogle Scholar
  114. 114.
    Kumalo HM, Bhakat S, Soliman ME (2016) Investigation of flap flexibility of β-secretase using molecular dynamic simulations. J Biomol Struct Dyn 34:1008–1019Google Scholar
  115. 115.
    Xu Y, Li M, Greenblatt H, Chen W, Paz A, Dym O, Peleg Y, Chen T, Shen X, He J, Jiang H, Silman I, Sussman JL (2012) Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations. Acta Crystallogr Sect D 68:13–25CrossRefGoogle Scholar
  116. 116.
    Lv Z, Chu Y, Wang Y (2015) HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS 7:95–104Google Scholar
  117. 117.
    Mesecar AD, Stoddard BL, Koshland DE (1997) Orbital steering in the catalytic power of enzymes: small structural changes with large catalytic consequences. Science 277:202–206CrossRefGoogle Scholar
  118. 118.
    Falke JJ (2002) Enzymology: a moving story. Science 295:1480–1481CrossRefGoogle Scholar
  119. 119.
    Benkovic SJ, Hammes-Schiffer S (2003) A perspective on enzyme catalysis. Science 301:1196–1202CrossRefGoogle Scholar
  120. 120.
    Bhabha G, Lee J, Ekiert DC, Gam J, Wilson, IA, Dyson HJ, Benkovic SJ, Wright PE (2011) A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis. Science 332:234–238CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Lara McGillewie
    • 1
  • Muthusamy Ramesh
    • 1
  • Mahmoud E. Soliman
    • 1
  1. 1.Molecular Modelling & Drug Design Research Group, School of Health SciencesUniversity of KwaZulu-Natal (UKZN)DurbanSouth Africa

Personalised recommendations