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Transmembrane segment proteases

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Summary

Transmembrane segment proteases comprise a novel class of proteases that cleave substrates within hydrophobic membrane-spanning segments. They cleave in parts of proteins that upon first glance should be protected by the hydrophobic environment of the lipid bilayer. At present, no such protease has been isolated and biochemically characterized. They are defined according to the appearance of the respective cleavage products. All trans-membrane segment proteases seem to participate in a regulated two-step proteolytic process that plays a central role in cellular regulation or is part of a protein degradation pathway.

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Abbreviations

β-APP:

β-amyloid precursor protein

S1P:

site-1 protease

S2P:

site-2 protease

SPase:

signal peptidase

SPPase:

signal peptide peptidase

SREBP:

sterol regulatory element-binding protein

SCAP SREBP:

cleavage-activating protein

References

  • Braud VM, Allan DSJ, O'Callaghan CA, Söderström K, D'Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391: 795–799

    Google Scholar 

  • Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89: 331–340

    Google Scholar 

  • Bunnell WL, Pham HV, Glabe CG (1998) γ-Secretase cleavage is distinct from endoplasmic reticulum degradation of the transmembrane domain of the amyloid precursor protein. J Biol Chem 273: 31947–31955

    Google Scholar 

  • Dalbey RE, Lively MO, Bron S, von Heijne G (1997) The chemistry and enzymology of the type I signal peptidases. Protein Sci 6: 1129–1138

    Google Scholar 

  • De Strooper B, Beullens M, Contrares B, Levensque L, Craessaerts K, Cordeil B, Moechars D, Bollen M, Fraser P, George-Hyslop PS, Van Leuven F (1997) Phosphorylation, subcellular localization and membrane orientation of the Alzheimer's disease-associated presenilins. J Biol Chem 272: 3590–3598

    Google Scholar 

  • Duncan EA, Davé UP, Sakai J, Goldstein JL, Brown MS (1998) Second-site cleavage in sterol regulatory element-binding protein occurs at transmembrane junction determined by cystein panning. J Biol Chem 273: 17801–17809

    Google Scholar 

  • Evans EA, Gilmore R, Blobel G (1986) Purification of microsomal signal peptidase as a complex. Proc Natl Acad Sci USA 83: 581–585

    Google Scholar 

  • Haass C (1996) Presenile because of presenilin: the presenilin genes and early onset Alzheimer's disease. Curr Opin Neurol 9: 254–259

    Google Scholar 

  • Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides. Nat Med 3: 1016–1020

    Google Scholar 

  • Hoyt DW, Girasch LM (1991) Hydrophobie content and lipid interaction of wild-type and mutant OmpA signal peptides correlate with their in vivo function. Biochemistry 30: 10155–10163

    Google Scholar 

  • Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13: 45–53

    Google Scholar 

  • Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR (1995) Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83: 129–135

    Google Scholar 

  • Killian JA, de Jong AM, Bijvelt J, Verkleij AJ, de Kruijff B (1990) Induction of non-bilayer lipid structures by functional signal peptides. EMBO J 9: 815–819

    Google Scholar 

  • Klappa P, Dierks T, Zimmermann R (1996) Cyclosporin A inhibits the degradation of signal sequences after processing of presecretory proteins by signal peptidase. Eur J Biochem 239: 509–518

    Google Scholar 

  • Koo EH, Squazzo SL (1994) Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem 269: 17386–17389

    Google Scholar 

  • Lee SJ, Liyanage U Bickel PE, Xia W, Lansburg PT Jr, Kosik KS (1998) A detergent-insoluble membrane compartment contains A beta in vivo. Nat Med 4: 730–734

    Google Scholar 

  • Leonhard K, Herrmann JM, Stuart RA, Mannhaupt G, Neupert W, Langer T (1996) AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria. EMBO J 15: 4218–4229

    Google Scholar 

  • Long EO (1998) Signal sequences stop killer cells. Nature 391: 740–743

    Google Scholar 

  • Lyko F, Martoglio B, Jungnickel B, Rapoport TA, Dobberstein B (1995) Signal sequence processing in rough microsomes. J Biol Chem 270: 19873–19878

    Google Scholar 

  • Martoglio B, Dobberstein B (1998) Signal sequences: more than just greasy peptides. Trends Cell Biol 8: 410–415

    Google Scholar 

  • —, Graf R, Dobberstein B (1997) Signal sequence fragments of pre-prolactin and HIV-1 p-gp160 interact with calmodulin. EMBO J 22: 6636–6645

    Google Scholar 

  • Moriyama T, Sather SK, McGee TP, Simoni RD (1998) Degradation of HMG-CoA reductase in vitro: cleavage in the membrane domain by a membrane-bound cystein protease. J Biol Chem 273: 22037–22043

    Google Scholar 

  • Nohturfft A, Brown MS, Goldstein JL (1998) Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J Biol Chem 273: 17243–17250

    Google Scholar 

  • Paetzel M, Dalbey RE, Strynadka NCJ (1998) Cristal structure of a bacterial signal peptidase in complex with a β-lactam inhibitor. Nature 396: 186–190

    Google Scholar 

  • Rapoport T, Jungnickel B, Kutay U (1996) Protein translocation across the eukaryotic endoplasmic reticulum and bacterial inner membranes. Annu Rev Biochem 65: 271–303

    Google Scholar 

  • Rawson RB, Zelenski NG, Nijhawan D, Ye J, Sakai J, Hasan MT, Chang TY, Brown MS, Goldstein JL (1997) Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol Cell 1: 47–57

    Google Scholar 

  • Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL (1996) Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 85: 1037–1046

    Google Scholar 

  • —, Nohturfft A, Cheng A, Ho YK, Brown MS, Goldstein JL (1997) Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J Biol Chem 272: 20213–20221

    Google Scholar 

  • —, Rawson RB, Espendshade PS, Cheng D, Seegmiller AC, Goldstein JL, Brown MS (1998) Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Mol Cell 2: 505–514

    Google Scholar 

  • Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunol Today 13: 136–142

    Google Scholar 

  • Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393: 382–386

    Google Scholar 

  • Selkoe DJ (1998) The cell biology of ρ-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol 8: 447–453

    Google Scholar 

  • Shoji M, Golde TE, Ghiso J, Chung TT, Estus S, Shaffler LM, Cai XD, McKay DM, Tintner R, Frangione B, Younkin SG (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258: 126–129

    Google Scholar 

  • van Klompenburg W, de Kruijff B (1998) The role of anionic lipids in protein insertion and translocation in bacterial membranes. J Membr Biol 162: 1–7

    Google Scholar 

  • Walter P, Johnson AE (1994) Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane. Annu Rev Cell Biol 10: 87–119

    Google Scholar 

  • Weidemann A, Paliga K, Durrwang U, Czech C, Evin G, Masters CL, Beyreuther K (1997) Formation of stable complexes between two Alzheimer's disease gene products: presenilin-2 and beta-amyloid precursor protein. Nat Med 3: 328–332

    Google Scholar 

  • Yang Y, Turner RS, Gaut JR (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Aβ40 and Aβ42 secretion. J Biol Chem 273: 25552–25555

    Google Scholar 

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  1. Institut für Biochemie II, ETH-Zentrum, Universitätstrasse 16, CH-8092, Zürich, Switzerland

    B. Martoglio

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  1. B. Martoglio
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Martoglio, B. Transmembrane segment proteases. Protoplasma 207, 141–146 (1999). https://doi.org/10.1007/BF01282993

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  • DOI: https://doi.org/10.1007/BF01282993

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