Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding

  • Franka Scharfenberg
  • Fred Armbrust
  • Liana Marengo
  • Claus PietrzikEmail author
  • Christoph Becker-PaulyEmail author


Alzheimer’s Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-β (Aβ) plaques are one of the pathological hallmarks in AD patient brains. Aβ accumulates in the brain upon sequential, proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases. However, so far disease-modifying drugs targeting β- and γ-secretase pathways seeking a decrease in the production of toxic Aβ peptides have failed in clinics. It has been demonstrated that the metalloproteinase meprin β acts as an alternative β-secretase, capable of generating truncated Aβ2–x peptides that have been described to be increased in AD patients. This indicates an important β-site cleaving enzyme 1 (BACE-1)-independent contribution of the metalloprotease meprin β within the amyloidogenic pathway and may lead to novel drug targeting avenues. However, meprin β itself is embedded in a complex regulatory network. Remarkably, the anti-amyloidogenic α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a direct competitor for APP at the cell surface, but also a sheddase of inactive pro-meprin β. Overall, we highlight the current cellular, molecular and structural understanding of meprin β as alternative β-secretase within the complex protease web, regulating APP processing in health and disease.


Meprin β ADAM10 APP β-secretase Alzheimer’s disease 



Alzheimer’s disease


Amyloid precursor protein

Amyloid-βADAM; a disintegrin and metalloproteinase domain-containing protein


β-Site cleaving enzyme 1


Presenilin 1 and 2





This work was supported by the Alzheimer Forschung Initiative e.V. (#18007) and the Deutsche Forschungsgemeinschaft (DFG) Project-number 125440785 SFB 877 (Proteolysis as a Regulatory Event in Pathophysiology, Projects A9 and A15) and BE 4086/2-2 (C.B.-P.).


  1. 1.
    Broder C, Becker-Pauly C (2013) The metalloproteases meprin alpha and meprin beta: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. Biochem J 450(2):253–264. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bode W, Grams F, Reinemer P, Gomis-Ruth FX, Baumann U, McKay DB, Stocker W (1996) The metzincin-superfamily of zinc-peptidases. Adv Exp Med Biol 389:1–11CrossRefPubMedGoogle Scholar
  3. 3.
    Gomis-Ruth FX (2003) Structural aspects of the metzincin clan of metalloendopeptidases. Mol Biotechnol 24(2):157–202. CrossRefPubMedGoogle Scholar
  4. 4.
    Gomis-Ruth FX, Trillo-Muyo S, Stocker W (2012) Functional and structural insights into astacin metallopeptidases. Biol Chem 393(10):1027–1041. CrossRefPubMedGoogle Scholar
  5. 5.
    Becker-Pauly C, Barre O, Schilling O, Auf dem Keller U, Ohler A, Broder C, Schutte A, Kappelhoff R, Stocker W, Overall CM (2011) Proteomic analyses reveal an acidic prime side specificity for the astacin metalloprotease family reflected by physiological substrates. Mol Cell Proteomics 10(9):M111009233. CrossRefGoogle Scholar
  6. 6.
    Arnold P, Otte A (1864) Becker-Pauly C (2017) Meprin metalloproteases: molecular regulation and function in inflammation and fibrosis. Biochim Biophys Acta Mol Cell Res 11 Pt B:2096–2104. CrossRefGoogle Scholar
  7. 7.
    Becker-Pauly C, Pietrzik CU (2016) The metalloprotease meprin beta is an alternative beta-secretase of APP. Front Mol Neurosci 9:159. CrossRefPubMedGoogle Scholar
  8. 8.
    Arnold P, Boll I, Rothaug M, Schumacher N, Schmidt F, Wichert R, Schneppenheim J, Lokau J, Pickhinke U, Koudelka T, Tholey A, Rabe B, Scheller J, Lucius R, Garbers C, Rose-John S, Becker-Pauly C (2017) Meprin metalloproteases generate biologically active soluble interleukin-6 receptor to induce trans-signaling. Sci Rep 7:44053. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Banerjee S, Jin G, Bradley SG, Matters GL, Gailey RD, Crisman JM, Bond JS (2011) Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 300(2):G273–G282. CrossRefPubMedGoogle Scholar
  10. 10.
    Keiffer TR, Bond JS (2014) Meprin metalloproteases inactivate interleukin 6. J Biol Chem 289(11):7580–7588. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Oneda B, Lods N, Lottaz D, Becker-Pauly C, Stocker W, Pippin J, Huguenin M, Ambort D, Marti HP, Sterchi EE (2008) Metalloprotease meprin beta in rat kidney: glomerular localization and differential expression in glomerulonephritis. PLoS One 3(5):e2278. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bylander JE, Ahmed F, Conley SM, Mwiza JM, Ongeri EM (2017) Meprin metalloprotease deficiency associated with higher mortality rates and more severe diabetic kidney injury in mice with STZ-induced type 1 diabetes. J Diabetes Res 2017:9035038. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Alidori S, Akhavein N, Thorek DL, Behling K, Romin Y, Queen D, Beattie BJ, Manova-Todorova K, Bergkvist M, Scheinberg DA, McDevitt MR (2016) Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury. Sci Transl Med 8(331):331ra339. CrossRefGoogle Scholar
  14. 14.
    Bedau T, Peters F, Prox J, Arnold P, Schmidt F, Finkernagel M, Kollmann S, Wichert R, Otte A, Ohler A, Stirnberg M, Lucius R, Koudelka T, Tholey A, Biasin V, Pietrzik CU, Kwapiszewska G, Becker-Pauly C (2017) Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin beta and promotes transendothelial cell migration. FASEB J 31(3):1226–1237. CrossRefPubMedGoogle Scholar
  15. 15.
    Bedau T, Schumacher N, Peters F, Prox J, Arnold P, Koudelka T, Helm O, Schmidt F, Rabe B, Jentzsch M, Rosenstiel P, Sebens S, Tholey A, Rose-John S, Becker-Pauly C (2017) Cancer-associated mutations in the canonical cleavage site do not influence CD99 shedding by the metalloprotease meprin beta but alter cell migration in vitro. Oncotarget 8(33):54873–54888. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kruse MN, Becker C, Lottaz D, Kohler D, Yiallouros I, Krell HW, Sterchi EE, Stocker W (2004) Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem J 378(Pt 2):383–389. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Broder C, Arnold P, Vadon-Le Goff S, Konerding MA, Bahr K, Muller S, Overall CM, Bond JS, Koudelka T, Tholey A, Hulmes DJ, Moali C, Becker-Pauly C (2013) Metalloproteases meprin alpha and meprin beta are C- and N-procollagen proteinases important for collagen assembly and tensile strength. Proc Natl Acad Sci USA 110(35):14219–14224. CrossRefPubMedGoogle Scholar
  18. 18.
    Kronenberg D, Bruns BC, Moali C, Vadon-Le Goff S, Sterchi EE, Traupe H, Bohm M, Hulmes DJ, Stocker W, Becker-Pauly C (2010) Processing of procollagen III by meprins: new players in extracellular matrix assembly? J Invest Dermatol 130(12):2727–2735. CrossRefPubMedGoogle Scholar
  19. 19.
    Schutte A, Ermund A, Becker-Pauly C, Johansson ME, Rodriguez-Pineiro AM, Backhed F, Muller S, Lottaz D, Bond JS, Hansson GC (2014) Microbial-induced meprin beta cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc Natl Acad Sci USA 111(34):12396–12401. CrossRefPubMedGoogle Scholar
  20. 20.
    Johansson ME, Hansson GC (2016) Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol 16(10):639–649. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wichert R, Ermund A, Schmidt S, Schweinlin M, Ksiazek M, Arnold P, Knittler K, Wilkens F, Potempa B, Rabe B, Stirnberg M, Lucius R, Bartsch JW, Nikolaus S, Falk-Paulsen M, Rosenstiel P, Metzger M, Rose-John S, Potempa J, Hansson GC, Dempsey PJ, Becker-Pauly C (2017) Mucus detachment by host metalloprotease meprin beta requires shedding of its inactive Pro-form, which is abrogated by the pathogenic protease RgpB. Cell Rep 21(8):2090–2103. CrossRefPubMedGoogle Scholar
  22. 22.
    Jackle F, Schmidt F, Wichert R, Arnold P, Prox J, Mangold M, Ohler A, Pietrzik CU, Koudelka T, Tholey A, Gutschow M, Stirnberg M, Becker-Pauly C (2015) Metalloprotease meprin beta is activated by transmembrane serine protease matriptase-2 at the cell surface thereby enhancing APP shedding. Biochem J 470(1):91–103. CrossRefPubMedGoogle Scholar
  23. 23.
    Bien J, Jefferson T, Causevic M, Jumpertz T, Munter L, Multhaup G, Weggen S, Becker-Pauly C, Pietrzik CU (2012) The metalloprotease meprin beta generates amino terminal-truncated amyloid beta peptide species. J Biol Chem 287(40):33304–33313. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Moller HJ, Graeber MB (1998) The case described by Alois Alzheimer in 1911. Historical and conceptual perspectives based on the clinical record and neurohistological sections. Eur Arch Psychiatry Clin Neurosci 248(3):111–122CrossRefPubMedGoogle Scholar
  25. 25.
    Murphy MP, LeVine H 3rd (2010) Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis 19(1):311–323. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sengupta U, Nilson AN, Kayed R (2016) The role of amyloid-beta oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 6:42–49. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP (1997) A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem 68(1):255–264CrossRefPubMedGoogle Scholar
  28. 28.
    Abramov AY, Canevari L, Duchen MR (2004) Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture. Biochim Biophys Acta 1742(1–3):81–87. CrossRefPubMedGoogle Scholar
  29. 29.
    McLaurin J, Chakrabartty A (1996) Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity. J Biol Chem 271(43):26482–26489CrossRefPubMedGoogle Scholar
  30. 30.
    Han SH, Park JC, Mook-Jung I (2016) Amyloid beta-interacting partners in Alzheimer’s disease: from accomplices to possible therapeutic targets. Prog Neurobiol 137:17–38. CrossRefPubMedGoogle Scholar
  31. 31.
    Venugopal C, Demos CM, Rao KS, Pappolla MA, Sambamurti K (2008) Beta-secretase: structure, function, and evolution. CNS Neurol Disord Drug Targets 7(3):278–294CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bohm C, Chen F, Sevalle J, Qamar S, Dodd R, Li Y, Schmitt-Ulms G, Fraser PE, St George-Hyslop PH (2015) Current and future implications of basic and translational research on amyloid-beta peptide production and removal pathways. Mol Cell Neurosci 66(Pt A):3–11. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Amyloid beta -protein (Abeta) assembly: abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci USA 100(1):330–335. CrossRefPubMedGoogle Scholar
  34. 34.
    Beglopoulos V, Sun X, Saura CA, Lemere CA, Kim RD, Shen J (2004) Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem 279(45):46907–46914. CrossRefPubMedGoogle Scholar
  35. 35.
    Sun L, Zhou R, Yang G, Shi Y (2017) Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase. Proc Natl Acad Sci USA 114(4):E476–E485. CrossRefPubMedGoogle Scholar
  36. 36.
    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 beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3):231–232. CrossRefPubMedGoogle Scholar
  37. 37.
    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(3):233–234. CrossRefPubMedGoogle Scholar
  38. 38.
    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(5440):735–741CrossRefPubMedGoogle Scholar
  39. 39.
    Vassar R (2002) Beta-secretase (BACE) as a drug target for Alzheimer’s disease. Adv Drug Deliv Rev 54(12):1589–1602CrossRefPubMedGoogle Scholar
  40. 40.
    Nishitomi K, Sakaguchi G, Horikoshi Y, Gray AJ, Maeda M, Hirata-Fukae C, Becker AG, Hosono M, Sakaguchi I, Minami SS, Nakajima Y, Li HF, Takeyama C, Kihara T, Ota A, Wong PC, Aisen PS, Kato A, Kinoshita N, Matsuoka Y (2006) BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild-type mice. J Neurochem 99(6):1555–1563. CrossRefPubMedGoogle Scholar
  41. 41.
    Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82(12):4245–4249CrossRefPubMedGoogle Scholar
  42. 42.
    Wiltfang J, Esselmann H, Cupers P, Neumann M, Kretzschmar H, Beyermann M, Schleuder D, Jahn H, Ruther E, Kornhuber J, Annaert W, De Strooper B, Saftig P (2001) Elevation of beta-amyloid peptide 2-42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J Biol Chem 276(46):42645–42657. CrossRefPubMedGoogle Scholar
  43. 43.
    Kummer MP, Heneka MT (2014) Truncated and modified amyloid-beta species. Alzheimers Res Ther 6(3):28. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bibl M, Gallus M, Welge V, Esselmann H, Wiltfang J (2012) Aminoterminally truncated and oxidized amyloid-beta peptides in the cerebrospinal fluid of Alzheimer’s disease patients. J Alzheimers Dis 29(4):809–816. CrossRefPubMedGoogle Scholar
  45. 45.
    Schechter I, Ziv E (2011) Cathepsins S, B and L with aminopeptidases display beta-secretase activity associated with the pathogenesis of Alzheimer’s disease. Biol Chem 392(6):555–569. CrossRefPubMedGoogle Scholar
  46. 46.
    Hook G, Yu J, Toneff T, Kindy M, Hook V (2014) Brain pyroglutamate amyloid-beta is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer’s disease therapeutic. J Alzheimers Dis 41(1):129–149. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Munger JS, Haass C, Lemere CA, Shi GP, Wong WS, Teplow DB, Selkoe DJ, Chapman HA (1995) Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S. Biochem J 311(Pt 1):299–305CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Hamazaki H (1996) Cathepsin D is involved in the clearance of Alzheimer’s beta-amyloid protein. FEBS Lett 396(2–3):139–142CrossRefPubMedGoogle Scholar
  49. 49.
    Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J, Wang X, Yu G, Esposito L, Mucke L, Gan L (2006) Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron 51(6):703–714. CrossRefPubMedGoogle Scholar
  50. 50.
    Letronne F, Laumet G, Ayral AM, Chapuis J, Demiautte F, Laga M, Vandenberghe ME, Malmanche N, Leroux F, Eysert F, Sottejeau Y, Chami L, Flaig A, Bauer C, Dourlen P, Lesaffre M, Delay C, Huot L, Dumont J, Werkmeister E, Lafont F, Mendes T, Hansmannel F, Dermaut B, Deprez B, Herard AS, Dhenain M, Souedet N, Pasquier F, Tulasne D, Berr C, Hauw JJ, Lemoine Y, Amouyel P, Mann D, Deprez R, Checler F, Hot D, Delzescaux T, Gevaert K, Lambert JC (2016) ADAM30 downregulates APP-Linked defects through cathepsin D activation in Alzheimer’s disease. EBioMedicine 9:278–292. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Sevalle J, Amoyel A, Robert P, Fournie-Zaluski MC, Roques B, Checler F (2009) Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide. J Neurochem 109(1):248–256. CrossRefPubMedGoogle Scholar
  52. 52.
    Hosoda R, Saido TC, Otvos L Jr, Arai T, Mann DM, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Quantification of modified amyloid beta peptides in Alzheimer disease and down syndrome brains. J Neuropathol Exp Neurol 57(11):1089–1095CrossRefPubMedGoogle Scholar
  53. 53.
    Schlenzig D, Cynis H, Hartlage-Rubsamen M, Zeitschel U, Menge K, Fothe A, Ramsbeck D, Spahn C, Wermann M, Rossner S, Buchholz M, Schilling S, Demuth HU (2018) Dipeptidyl-peptidase activity of meprin beta links N-truncation of abeta with glutaminyl cyclase-catalyzed pGlu-abeta formation. J Alzheimers Dis 66(1):359–375. CrossRefPubMedGoogle Scholar
  54. 54.
    Schonherr C, Bien J, Isbert S, Wichert R, Prox J, Altmeppen H, Kumar S, Walter J, Lichtenthaler SF, Weggen S, Glatzel M, Becker-Pauly C, Pietrzik CU (2016) Generation of aggregation prone N-terminally truncated amyloid beta peptides by meprin beta depends on the sequence specificity at the cleavage site. Mol Neurodegener 11:19. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Jefferson T, Causevic M, Auf dem Keller U, Schilling O, Isbert S, Geyer R, Maier W, Tschickardt S, Jumpertz T, Weggen S, Bond JS, Overall CM, Pietrzik CU, Becker-Pauly C (2011) Metalloprotease meprin beta generates nontoxic N-terminal amyloid precursor protein fragments in vivo. J Biol Chem 286(31):27741–27750. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Muller UC, Deller T, Korte M (2017) Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 18(5):281–298. CrossRefGoogle Scholar
  57. 57.
    Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360(6405):672–674. CrossRefPubMedGoogle Scholar
  58. 58.
    Elder GA, Gama Sosa MA, De Gasperi R (2010) Transgenic mouse models of Alzheimer’s disease. Mt Sinai J Med 77(1):69–81. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ohshima Y, Taguchi K, Mizuta I, Tanaka M, Tomiyama T, Kametani F, Yabe-Nishimura C, Mizuno T, Tokuda T (2018) Mutations in the beta-amyloid precursor protein in familial Alzheimer’s disease increase Abeta oligomer production in cellular models. Heliyon 4(1):e00511. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF (2004) BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41(1):27–33CrossRefPubMedGoogle Scholar
  61. 61.
    Patel T, Brookes KJ, Turton J, Chaudhury S, Guetta-Baranes T, Guerreiro R, Bras J, Hernandez D, Singleton A, Francis PT, Hardy J, Morgan K (2017) Whole-exome sequencing of the BDR cohort: evidence to support the role of the PILRA gene in Alzheimer’s disease. Neuropathol Appl Neurobiol 44:506–521. CrossRefGoogle Scholar
  62. 62.
    Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF (2010) ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 29(17):3020–3032. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Ohler A, Debela M, Wagner S, Magdolen V, Becker-Pauly C (2010) Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biol Chem 391(4):455–460. CrossRefPubMedGoogle Scholar
  64. 64.
    Jefferson T, Auf dem Keller U, Bellac C, Metz VV, Broder C, Hedrich J, Ohler A, Maier W, Magdolen V, Sterchi E, Bond JS, Jayakumar A, Traupe H, Chalaris A, Rose-John S, Pietrzik CU, Postina R, Overall CM, Becker-Pauly C (2013) The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin beta and ADAM10. Cell Mol Life Sci 70(2):309–333. CrossRefPubMedGoogle Scholar
  65. 65.
    Herzog C, Haun RS, Ludwig A, Shah SV, Kaushal GP (2014) ADAM10 is the major sheddase responsible for the release of membrane-associated meprin A. J Biol Chem 289(19):13308–13322. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Banerjee S, Bond JS (2008) Prointerleukin-18 is activated by meprin beta in vitro and in vivo in intestinal inflammation. J Biol Chem 283(46):31371–31377. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457(7232):981–989. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Olsen O, Kallop DY, McLaughlin T, Huntwork-Rodriguez S, Wu Z, Duggan CD, Simon DJ, Lu Y, Easley-Neal C, Takeda K, Hass PE, Jaworski A, O’Leary DD, Weimer RM, Tessier-Lavigne M (2014) Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of beta-secretase. J Neurosci 34(19):6438–6447. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Peron R, Vatanabe IP, Manzine PR, Camins A, Cominetti MR (2018) Alpha-secretase ADAM10 regulation: insights into Alzheimer’s disease Treatment. Pharmaceuticals 11:1. CrossRefGoogle Scholar
  70. 70.
    Wasco W, Bupp K, Magendantz M, Gusella JF, Tanzi RE, Solomon F (1992) Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci USA 89(22):10758–10762CrossRefPubMedGoogle Scholar
  71. 71.
    Pandey P, Sliker B, Peters HL, Tuli A, Herskovitz J, Smits K, Purohit A, Singh RK, Dong J, Batra SK, Coulter DW, Solheim JC (2016) Amyloid precursor protein and amyloid precursor-like protein 2 in cancer. Oncotarget 7(15):19430–19444. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Jacobsen KT, Iverfeldt K (2009) Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors. Cell Mol Life Sci 66(14):2299–2318. CrossRefPubMedGoogle Scholar
  73. 73.
    Sprecher CA, Grant FJ, Grimm G, O’Hara PJ, Norris F, Norris K, Foster DC (1993) Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family. Biochemistry 32(17):4481–4486CrossRefPubMedGoogle Scholar
  74. 74.
    Wasco W, Gurubhagavatula S, Paradis MD, Romano DM, Sisodia SS, Hyman BT, Neve RL, Tanzi RE (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nat Genet 5(1):95–100. CrossRefPubMedGoogle Scholar
  75. 75.
    Coulson EJ, Paliga K, Beyreuther K, Masters CL (2000) What the evolution of the amyloid protein precursor supergene family tells us about its function. Neurochem Int 36(3):175–184CrossRefPubMedGoogle Scholar
  76. 76.
    Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW (1999) Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nat Struct Biol 6(4):327–331. CrossRefPubMedGoogle Scholar
  77. 77.
    Barnham KJ, McKinstry WJ, Multhaup G, Galatis D, Morton CJ, Curtain CC, Williamson NA, White AR, Hinds MG, Norton RS, Beyreuther K, Masters CL, Parker MW, Cappai R (2003) Structure of the Alzheimer’s disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem 278(19):17401–17407. CrossRefPubMedGoogle Scholar
  78. 78.
    Kong GK, Adams JJ, Harris HH, Boas JF, Curtain CC, Galatis D, Masters CL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW (2007) Structural studies of the Alzheimer’s amyloid precursor protein copper-binding domain reveal how it binds copper ions. J Mol Biol 367(1):148–161. CrossRefPubMedGoogle Scholar
  79. 79.
    Dahms SO, Hoefgen S, Roeser D, Schlott B, Guhrs KH, Than ME (2010) Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein. Proc Natl Acad Sci USA 107(12):5381–5386. CrossRefPubMedGoogle Scholar
  80. 80.
    Kang J, Muller-Hill B (1990) Differential splicing of Alzheimer’s disease amyloid A4 precursor RNA in rat tissues: pre A4(695) mRNA is predominantly produced in rat and human brain. Biochem Biophys Res Commun 166(3):1192–1200CrossRefPubMedGoogle Scholar
  81. 81.
    Weidemann A, Konig G, Bunke D, Fischer P, Salbaum JM, Masters CL, Beyreuther K (1989) Identification, biogenesis, and localization of precursors of Alzheimer’s disease A4 amyloid protein. Cell 57(1):115–126CrossRefPubMedGoogle Scholar
  82. 82.
    Ninomiya H, Roch JM, Sundsmo MP, Otero DA, Saitoh T (1993) Amino acid sequence RERMS represents the active domain of amyloid beta/A4 protein precursor that promotes fibroblast growth. J Cell Biol 121(4):879–886CrossRefPubMedGoogle Scholar
  83. 83.
    Ninomiya H, Roch JM, Jin LW, Saitoh T (1994) Secreted form of amyloid beta/A4 protein precursor (APP) binds to two distinct APP binding sites on rat B103 neuron-like cells through two different domains, but only one site is involved in neuritotropic activity. J Neurochem 63(2):495–500CrossRefPubMedGoogle Scholar
  84. 84.
    Pawlik M, Otero DA, Park M, Fischer WH, Levy E, Saitoh T (2007) Proteins that bind to the RERMS region of beta amyloid precursor protein. Biochem Biophys Res Commun 355(4):907–912. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Gralle M, Ferreira ST (2007) Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts. Prog Neurobiol 82(1):11–32. CrossRefPubMedGoogle Scholar
  86. 86.
    Reinhard C, Hebert SS, De Strooper B (2005) The amyloid-beta precursor protein: integrating structure with biological function. EMBO J 24(23):3996–4006. CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Turner PR, O’Connor K, Tate WP, Abraham WC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70(1):1–32CrossRefPubMedGoogle Scholar
  88. 88.
    Wang Y, Ha Y (2004) The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell 15(3):343–353. CrossRefPubMedGoogle Scholar
  89. 89.
    Pahlsson P, Shakin-Eshleman SH, Spitalnik SL (1992) N-linked glycosylation of beta-amyloid precursor protein. Biochem Biophys Res Commun 189(3):1667–1673CrossRefPubMedGoogle Scholar
  90. 90.
    Hoefgen S, Dahms SO, Oertwig K, Than ME (2015) The amyloid precursor protein shows a pH-dependent conformational switch in its E1 domain. J Mol Biol 427(2):433–442. CrossRefPubMedGoogle Scholar
  91. 91.
    Hoefgen S, Coburger I, Roeser D, Schaub Y, Dahms SO, Than ME (2014) Heparin induced dimerization of APP is primarily mediated by E1 and regulated by its acidic domain. J Struct Biol 187(1):30–37. CrossRefPubMedGoogle Scholar
  92. 92.
    Dahms SO, Konnig I, Roeser D, Guhrs KH, Mayer MC, Kaden D, Multhaup G, Than ME (2012) Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. J Mol Biol 416(3):438–452. CrossRefPubMedGoogle Scholar
  93. 93.
    Keil C, Huber R, Bode W, Than ME (2004) Cloning, expression, crystallization and initial crystallographic analysis of the C-terminal domain of the amyloid precursor protein APP. Acta Crystallogr D Biol Crystallogr 60(Pt 9):1614–1617. CrossRefPubMedGoogle Scholar
  94. 94.
    Dulubova I, Ho A, Huryeva I, Sudhof TC, Rizo J (2004) Three-dimensional structure of an independently folded extracellular domain of human amyloid-beta precursor protein. Biochemistry 43(30):9583–9588. CrossRefPubMedGoogle Scholar
  95. 95.
    Lu JX, Yau WM, Tycko R (2011) Evidence from solid-state NMR for nonhelical conformations in the transmembrane domain of the amyloid precursor protein. Biophys J 100(3):711–719. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Botev A, Munter LM, Wenzel R, Richter L, Althoff V, Ismer J, Gerling U, Weise C, Koksch B, Hildebrand PW, Bittl R, Multhaup G (2011) The amyloid precursor protein C-terminal fragment C100 occurs in monomeric and dimeric stable conformations and binds gamma-secretase modulators. Biochemistry 50(5):828–835. CrossRefPubMedGoogle Scholar
  97. 97.
    Nadezhdin KD, Bocharova OV, Bocharov EV, Arseniev AS (2011) Structural and dynamic study of the transmembrane domain of the amyloid precursor protein. Acta Naturae 3(1):69–76PubMedPubMedCentralGoogle Scholar
  98. 98.
    Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47(36):9428–9446. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Sato T, Tang TC, Reubins G, Fei JZ, Fujimoto T, Kienlen-Campard P, Constantinescu SN, Octave JN, Aimoto S, Smith SO (2009) A helix-to-coil transition at the epsilon-cut site in the transmembrane dimer of the amyloid precursor protein is required for proteolysis. Proc Natl Acad Sci USA 106(5):1421–1426. CrossRefPubMedGoogle Scholar
  100. 100.
    Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR (2012) The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336(6085):1168–1171. CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    MacKenzie KR, Prestegard JH, Engelman DM (1997) A transmembrane helix dimer: structure and implications. Science 276(5309):131–133CrossRefPubMedGoogle Scholar
  102. 102.
    Javadpour MM, Eilers M, Groesbeek M, Smith SO (1999) Helix packing in polytopic membrane proteins: role of glycine in transmembrane helix association. Biophys J 77(3):1609–1618. CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Kim S, Jeon TJ, Oberai A, Yang D, Schmidt JJ, Bowie JU (2005) Transmembrane glycine zippers: physiological and pathological roles in membrane proteins. Proc Natl Acad Sci USA 102(40):14278–14283. CrossRefPubMedGoogle Scholar
  104. 104.
    Anderson SM, Mueller BK, Lange EJ, Senes A (2017) Combination of Calpha-H Hydrogen Bonds and van der Waals Packing Modulates the Stability of GxxxG-Mediated Dimers in Membranes. J Am Chem Soc 139(44):15774–15783. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Munter LM, Voigt P, Harmeier A, Kaden D, Gottschalk KE, Weise C, Pipkorn R, Schaefer M, Langosch D, Multhaup G (2007) GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42. EMBO J 26(6):1702–1712. CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Decock M, Stanga S, Octave JN, Dewachter I, Smith SO, Constantinescu SN, Kienlen-Campard P (2016) Glycines from the APP GXXXG/GXXXA transmembrane motifs promote formation of pathogenic abeta oligomers in cells. Front Aging Neurosci 8:107. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Yano Y, Kondo K, Watanabe Y, Zhang TO, Ho JJ, Oishi S, Fujii N, Zanni MT, Matsuzaki K (2017) GXXXG-Mediated Parallel and Antiparallel Dimerization of Transmembrane Helices and Its Inhibition by Cholesterol: single-Pair FRET and 2D IR Studies. Angew Chem Int Ed Engl 56(7):1756–1759. CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Yan Y, Xu TH, Harikumar KG, Miller LJ, Melcher K, Xu HE (2017) Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma-secretase cleavage sites. J Biol Chem 292(38):15826–15837. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Nadezhdin KD, Bocharova OV, Bocharov EV, Arseniev AS (2012) Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment. FEBS Lett 586(12):1687–1692. CrossRefPubMedGoogle Scholar
  110. 110.
    Chen W, Gamache E, Rosenman DJ, Xie J, Lopez MM, Li YM, Wang C (2014) Familial Alzheimer’s mutations within APPTM increase Abeta42 production by enhancing accessibility of epsilon-cleavage site. Nat Commun 5:3037. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Song Y, Hustedt EJ, Brandon S, Sanders CR (2013) Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein. Biochemistry 52(30):5051–5064. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Dominguez L, Foster L, Straub JE, Thirumalai D (2016) Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein. Proc Natl Acad Sci USA 113(36):E5281–5287. CrossRefPubMedGoogle Scholar
  113. 113.
    Dominguez L, Foster L, Meredith SC, Straub JE, Thirumalai D (2014) Structural heterogeneity in transmembrane amyloid precursor protein homodimer is a consequence of environmental selection. J Am Chem Soc 136(27):9619–9626. CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Pantelopulos GA, Straub JE, Thirumalai D, Sugita Y (2018) Structure of APP-C991-99 and implications for role of extra-membrane domains in function and oligomerization. Biochim Biophys Acta Biomembr 1860:1698–1708. CrossRefGoogle Scholar
  115. 115.
    Ramelot TA, Gentile LN, Nicholson LK (2000) Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors. Biochemistry 39(10):2714–2725CrossRefPubMedGoogle Scholar
  116. 116.
    Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T (2001) Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J Biol Chem 276(43):40353–40361. CrossRefPubMedGoogle Scholar
  117. 117.
    Yun M, Keshvara L, Park CG, Zhang YM, Dickerson JB, Zheng J, Rock CO, Curran T, Park HW (2003) Crystal structures of the Dab homology domains of mouse disabled 1 and 2. J Biol Chem 278(38):36572–36581. CrossRefPubMedGoogle Scholar
  118. 118.
    Zhang Z, Lee CH, Mandiyan V, Borg JP, Margolis B, Schlessinger J, Kuriyan J (1997) Sequence-specific recognition of the internalization motif of the Alzheimer’s amyloid precursor protein by the X11 PTB domain. EMBO J 16(20):6141–6150. CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Radzimanowski J, Simon B, Sattler M, Beyreuther K, Sinning I, Wild K (2008) Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2. EMBO Rep 9(11):1134–1140. CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Arolas JL, Broder C, Jefferson T, Guevara T, Sterchi EE, Bode W, Stocker W, Becker-Pauly C, Gomis-Ruth FX (2012) Structural basis for the sheddase function of human meprin beta metalloproteinase at the plasma membrane. Proc Natl Acad Sci USA 109(40):16131–16136. CrossRefPubMedGoogle Scholar
  121. 121.
    Peters F, Scharfenberg F, Colmorgen C, Armbrust F, Wichert R, Arnold P, Potempa B, Potempa J, Pietrzik CU, Hasler R, Rosenstiel P, Becker-Pauly C (2019) Tethering soluble meprin alpha in an enzyme complex to the cell surface affects IBD-associated genes. FASEB J 2019:fj201802391R. CrossRefGoogle Scholar
  122. 122.
    Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC (2017) Structural Basis for Regulated Proteolysis by the alpha-Secretase ADAM10. Cell 171(7):1638–1648 e1637. CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Liu L, Ding L, Rovere M, Wolfe MS, Selkoe DJ (2019) A cellular complex of BACE1 and gamma-secretase sequentially generates Abeta from its full-length precursor. J Cell Biol 218(2):644–663. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Unit for Degradomics of the Protease Web, Biochemical InstituteUniversity of KielKielGermany
  2. 2.Institute for PathobiochemistryUniversity Medical Center of the Johannes Gutenberg-University MainzMainzGermany

Personalised recommendations