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PreprintCited by 10Cellular transport and secretionEndoplasmic Reticulum Stress and DiseaseProtein Structure and Dynamics

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Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage

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Liaci, A. Manuel, Steigenberger, Barbara, Tamara, Sem, de Souza, Paulo Cesar Telles, Gröllers-Mulderij, Mariska, Ogrissek, Patrick, Marrink, Siewert J., Scheltema, Richard A., Förster, Friedrich·2020·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2020.11.11.378711

Preprint — published as 10.1016/j.molcel.2021.07.031

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Abstract

The signal peptidase complex (SPC) is an essential membrane complex in the endoplasmic reticulum (ER), where it removes signal peptides (SPs) from a large variety of secretory pre-proteins with exquisite specificity. Although the determinants of this process have been established empirically, the molecular details of SP recognition and removal remain elusive. Here, we show that the human SPC exists in two functional paralogs with distinct proteolytic subunits. We determined the atomic structures of both paralogs using electron cryo-microscopy and structural proteomics. The active site is formed by a catalytic triad and abuts the ER membrane, where a transmembrane window collectively formed by all subunits locally thins the bilayer. This unique architecture generates specificity for thousands of SPs based on the length of their hydrophobic segments.

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  1. 10.1083/jcb.67.3.835 · DOI
  2. M. Uhlén , L. Fagerberg , B. M. Hallström , et al., Tissue-based map of the human proteome. Science (80-.). 347 (2015) (available at https://www.proteinatlas.org/). · DOI
  3. 10.1128/JVI.01506-07 · DOI
  4. 10.1371/journal.ppat.1003800 · DOI
  5. 2017, The natural product cavinafungin selectively interferes with zika and dengue virus replication by inhibition of the host signal peptidase, Cell Rep, 19, 451, 10.1016/j.celrep.2017.03.071 · DOI
  6. 10.7554/eLife.20010 · DOI
  7. 10.1038/nature18625 · DOI
  8. 10.1073/pnas.83.3.581 · DOI
  9. 1990, Two subunits of the canine signal peptidase complex are homologous to yeast SEC11 protein, J. Biol. Chem, 265, 9512, 10.1016/S0021-9258(19)38879-9 · DOI
  10. 1992, Signal peptidase I of Bacillus subtilis: Patterns of conserved amino acids in prokaryotic and eukaryotic type I signal peptidases, EMBO J, 11, 2819, 10.1002/j.1460-2075.1992.tb05349.x · DOI
  11. 1993, A serine and a lysine residue implicated in the catalytic mechanism of the Escherichia coli leader peptidase, J. Biol. Chem, 268, 27349, 10.1016/S0021-9258(19)74256-2 · DOI
  12. 10.1038/24196 · DOI
  13. 10.1074/jbc.274.17.11519 · DOI
  14. 10.1021/cr010166y · DOI · Paper page
  15. H. Nielsen , K. D. Tsirigos , S. Brunak , et al., A brief history of protein sorting prediction. Protein J. 38 (2019), pp. 200–216.
  16. 10.1007/BF01868635 · DOI
  17. 10.1038/nrm2063 · DOI
  18. 10.1083/jcb.126.5.1127 · DOI
  19. 10.1074/jbc.M307542200 · DOI
  20. 10.1038/s41467-019-09078-0 · DOI
  21. 10.1073/pnas.1914677117 · DOI · Paper page
  22. 1993, Membrane topology and biogenesis of eukaryotic signal peptidase, J. Biol. Chem, 268, 5201, 10.1016/S0021-9258(18)53520-1 · DOI
  23. 10.1074/jbc.271.7.3925 · DOI
  24. 2019, PhoX: An IMAC-enrichable cross-linking reagent, ACS Cent. Sci, 5, 1514, 10.1021/acscentsci.9b00416 · DOI
  25. 10.1016/j.cub.2003.11.027 · DOI
  26. 1989, Purification and characterization of hen oviduct N(α)-acetyltransferase, J. Biol. Chem, 264, 13188, 10.1016/S0021-9258(18)51613-6 · DOI
  27. 10.1074/jbc.272.20.13159 · DOI
  28. 10.1074/jbc.272.20.13152 · DOI
  29. 10.1074/jbc.271.46.29094 · DOI
  30. 10.1074/jbc.M006126200 · DOI
  31. 10.1073/pnas.1210303109 · DOI
  32. 10.1074/jbc.271.28.16460 · DOI
  33. 10.1107/S2052252515019971 · DOI
  34. 10.1074/jbc.M401686200 · DOI
  35. 2014, Structure and mechanism of Escherichia coli type I signal peptidase, Biochim. Biophys. Acta - Mol. Cell Res, 1843, 1497, 10.1016/j.bbamcr.2013.12.003 · DOI
  36. 10.1021/cr040669e · DOI
  37. N. van Hilten , K. S. Stroh , H. J. Risselada , Membrane thinning induces sorting of lipids and the amphipathic lipid packing sensor (ALPS) protein motif. Front. Physiol. 11 (2020). · DOI
  38. 10.1126/science.abb5008 · DOI
  39. 1983, Hen oviduct signal peptidase is an integral membrane protein, J. Biol. Chem, 258, 9488, 10.1016/S0021-9258(17)44693-X · DOI
  40. 1986, Is phospholipid a required cofactor for the activity of mammalian signal peptidase?, FEBS Lett, 200, 343, 10.1016/0014-5793(86)81165-6 · DOI
  41. 10.1021/bi002903a · DOI
  42. 10.1007/978-3-540-69828-9_12 · DOI
  43. 10.1038/ncomms9403 · DOI
  44. 10.1126/science.aad4992 · DOI
  45. 10.1038/nature17163 · DOI
  46. 10.1038/ncomms14516 · DOI
  47. 10.1016/0092-8674(93)90483-7 · DOI
  48. S. Pfeffer , J. Dudek , M. Gogala , et al., Structure of the mammalian oligosaccharyl-transferase complex in the native ER protein translocon. Nat. Commun. 5 (2014) (available at http://www.nature.com/doifinder/10.1038/ncomms40 72). · DOI
  49. 10.1038/ncomms14516 · DOI
  50. 10.1083/jcb.141.4.887 · DOI
  51. 10.1111/j.1749-6632.1980.tb47268.x · DOI
  52. 1983, Quantitative assay for signal peptidase, Methods Enzymol, 96, 784, 10.1016/S0076-6879(83)96066-4 · DOI
  53. 2013, Signal Peptidase (Eukaryote), Handb. Proteolytic Enzym, 3, 3512
  54. 10.1074/mcp.M114.043489 · DOI
  55. 10.1021/acs.jproteome.7b00602 · DOI
  56. 10.1038/nbt.1511 · DOI · Paper page
  57. 10.1093/nar/gkl1107 · DOI
  58. 10.1038/s41467-019-13889-6 · DOI · Paper page
  59. 10.1021/ac403115c · DOI
  60. 10.1038/s41596-018-0074-x · DOI
  61. 2019, Real-time cryo-electron microscopy data preprocessing with Warp, Nat. Methods, 16, 1146, 10.1038/s41592-019-0580-y · DOI
  62. 10.1016/j.jmb.2011.11.010 · DOI
  63. 10.1038/nmeth.4193 · DOI
  64. 10.1016/j.jsb.2015.08.008 · DOI
  65. 2019, SPHIRE-crYOLO is a fast and accurate fully automated particle picker for cryo-EM, Commun. Biol, 2, 1
  66. 10.1002/jcc.20084 · DOI
  67. 10.1107/S0907444910007493 · DOI · Paper page
  68. 2018, Real-space refinement in PHENIX for cryo-EM and crystallography, Acta Crystallogr. Sect. D Struct. Biol, 74, 531, 10.1107/S2059798318006551 · DOI
  69. 10.1002/pro.3235 · DOI · Paper page
  70. 10.1093/nar/gkv332 · DOI
  71. 2019, NetSurfP-2.0: Improved prediction of protein structural features by integrated deep learning, Proteins Struct. Funct. Bioinforma, 87, 520, 10.1002/prot.25674 · DOI
  72. 10.1093/molbev/msy096 · DOI
  73. 10.1093/nar/gkw408 · DOI · Paper page
  74. 10.1021/jp071097f · DOI
  75. 2018, Capturing phase behavior of ternary lipid mixtures with a refined martini coarse-grained force field, J. Chem. Theory Comput, 14, 6050, 10.1021/acs.jctc.8b00496 · DOI
  76. 10.1016/j.cpc.2015.09.014 · DOI
  77. G. Bussi , D. Donadio , M. Parrinello , Canonical sampling through velocity rescaling. J. Chem. Phys. 126 (2007). · DOI
  78. 10.1063/1.328693 · DOI
  79. M. J. Abraham , T. Murtola , R. Schulz , et al., Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 1–2, 19–25 (2015). · DOI · Paper page
  80. 10.1038/nmeth.4067 · DOI
  81. 10.1021/jp101759q · DOI
  82. 10.1021/jp973084f · DOI
  83. 10.1021/ja00392a016 · DOI
  84. 10.1063/1.470117 · DOI
  85. 10.1063/1.464397 · DOI
  86. 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.3.CO;2-L · DOI
  87. 10.1021/acs.jctc.5b00935 · DOI
  88. 10.1021/ct400617g · DOI
  89. 10.1371/journal.pone.0131080 · DOI
  90. 10.1016/0263-7855(96)00018-5 · DOI · Paper page
  91. 2016, Collision-induced dissociation of electrosprayed protein complexes: An all-atom molecular dynamics model with mobile protons, J. Phys. Chem. B, 120, 5114, 10.1021/acs.jpcb.6b03035 · DOI
  92. 10.1021/ja0211508 · DOI

Metadata

Authors
Liaci, A. M., Steigenberger, B., Tamara, S., de Souza, P. C. T., Gröllers-Mulderij, M., Ogrissek, P., Marrink, S. J., Scheltema, R. A., & Förster, F.
Affiliations
  • Utrecht University (NL)
  • University of Groningen (NL)
Corresponding author
Förster, Friedrich
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2020-11-11
DOI
10.1101/2020.11.11.378711
OpenAlex
W3105131382
Cited by
10
References
3
Citations by year
2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • European Commission (823839, 724425, HORIZON2020)
  • Universiteit Utrecht
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (724425, 741.018.201)
  • Universitair Medisch Centrum Utrecht
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
signal peptidase complex, signal peptide cleavage, endoplasmic reticulum membrane, paralogs, catalytic triad, membrane thinning, cleavage specificity, protein structure

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