Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix
Open accessAbstract
Ectodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate's TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The protein encoded by SPPL2A is involved in noncanonical shedding of TNF-α, and PGRN has been described as a TNF receptor ligand and an antagonist of TNF-α signaling.
“The protein encoded by SPPL2A is involved in noncanonical shedding of TNF-α34, and PGRN has been described as a TNF receptor ligand and an antagonist of TNF-α signaling35.”
From New insights into the genetic etiology of Alzheimer’s disease and related dementias (2022) · cites this paper as [34]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Kabsch, W., & Sander, C. (1983) · Biopolymers · doi:10.1002/bip.360221211 · Cited by 15,320 · see citing works
NMR with Proteins and Nucleic Acids
Wüthrich, K. (1986) · Europhysics news · doi:10.1051/epn/19861701011 · Cited by 8,025 · see citing works
A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells
Black, R. A., Rauch, C. T., Kozlosky, C. J., Peschon, J. J., Slack, J. L., Wolfson, M. F., Castner, B. J., Stocking, K. L., Reddy, P., Srinivasan, S., et al. (1997) · Nature · doi:10.1038/385729a0 · Cited by 3,149 · see citing works
Relationship between nuclear magnetic resonance chemical shift and protein secondary structure
Wishart, D. S., Sykes, B. D., & Richards, F. M. (1991) · Journal of Molecular Biology · doi:10.1016/0022-2836(91)90214-q · Cited by 1,907 · see citing works
Spera, S., & Bax, A. (1991) · Journal of the American Chemical Society · doi:10.1021/ja00014a071 · Cited by 1,101 · see citing works
Regulation of tumour necrosis factor signalling: live or let die
Brenner, D., Blaser, H., & Mak, T. W. (2015) · Nature Reviews Immunology · doi:10.1038/nri3834 · Cited by 998 · see citing works
Hydrogen exchange mass spectrometry for studying protein structure and dynamics
Konermann, L., Pan, J., & Liu, Y. (2010) · Chemical Society Reviews · doi:10.1039/c0cs00113a · Cited by 842 · see citing works
Presenilin is required for activity and nuclear access of Notch in Drosophila
Struhl, G., & Greenwald, I. (1999) · Nature · doi:10.1038/19091 · Cited by 804 · see citing works
Regulation of tumour necrosis factor-α processing by a metalloproteinase inhibitor
McGeehan, G. M., Becherer, J. D., Bast, R. C., Boyer, C. M., CHAMPION, B. R., Connolly, K. M., Conway, J. G., Furdon, P. J., Karp, S. E., Kidao, S., et al. (1994) · Nature · doi:10.1038/370558a0 · Cited by 561 · see citing works
γ-Secretase: proteasome of the membrane?
Kopan, R., & Ilagan, M. X. G. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1406 · Cited by 554 · see citing works
Identification of Signal Peptide Peptidase, a Presenilin-Type Aspartic Protease
Weihofen, A., Binns, K. L., Lemberg, M. K., Ashman, K., & Martoglio, B. (2002) · Science · doi:10.1126/science.1070925 · Cited by 532 · see citing works
An atomic structure of human γ-secretase
Bai, X., Yan, C., Yang, G., Lu, P., Ma, D., Sun, L., Zhou, R., Scheres, S. H. W., & Shi, Y. (2015) · Nature · doi:10.1038/nature14892 · Cited by 499 · see citing works
The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol
Barrett, P. J., Song, Y., Horn, W. D. V., Hustedt, E. J., Schafer, J. M., Hadziselimovic, A., Beel, A. J., & Sanders, C. R. (2012) · Science · doi:10.1126/science.1219988 · Cited by 472 · see citing works
γ-secretase directly sheds the survival receptor BCMA from plasma cells
Laurent, S. A., Hoffmann, F. S., Kuhn, P.-H., Cheng, Q., Chu, Y., Schmidt-Supprian, M., Hauck, S. M., Schuh, E., Krumbholz, M., Rübsamen, H., et al. (2015) · Nature Communications · doi:10.1038/ncomms8333 · Cited by 377 · see citing works
Proline-induced Distortions of Transmembrane Helices
Cordes, F. S., Bright, J. N., & Sansom, M. S. P. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)01006-9 · Cited by 365 · see citing works
Hayward, S., & Lee, R. A. (2002) · Journal of Molecular Graphics and Modelling · doi:10.1016/s1093-3263(02)00140-7 · Cited by 305 · see citing works
Recognition of the amyloid precursor protein by human γ-secretase
Zhou, R., Yang, G., Guo, X., Zhou, Q., Lei, J., & Shi, Y. (2019) · Science · doi:10.1126/science.aaw0930 · Cited by 304 · see citing works
Lichtenthaler, S. F., Lemberg, M. K., & Fluhrer, R. (2018) · The EMBO Journal · doi:10.15252/embj.201899456 · Cited by 298 · see citing works
Self-citationEhlers, M. R., & Riordan, J. F. (1991) · Biochemistry · doi:10.1021/bi00106a001 · Cited by 281 · see citing works
Gray, T. M., & Matthews, B. W. (1984) · Journal of Molecular Biology · doi:10.1016/0022-2836(84)90446-7 · Cited by 254 · see citing works
Requirements for Signal Peptide Peptidase-Catalyzed Intramembrane Proteolysis
Lemberg, M. K., & Martoglio, B. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00655-x · Cited by 244 · see citing works
Schröder, B. A., Wrocklage, C., Hasilik, A., & Saftig, P. (2010) · PROTEOMICS · doi:10.1002/pmic.201000196 · Cited by 226 · see citing works
Friedmann, E., Hauben, E., Maylandt, K., Schleeger, S., Vreugde, S., Lichtenthaler, S. F., Kuhn, P., Stauffer, D., Rovelli, G., & Martoglio, B. (2006) · Nature Cell Biology · doi:10.1038/ncb1440 · Cited by 201 · see citing works
Mohan, M. J., Seaton, T., Mitchell, J. L., Howe, A., Blackburn, K., Burkhart, W., Moyer, M. B., Patel, I., Waitt, G. M., Becherer, J. D., et al. (2002) · Biochemistry · doi:10.1021/bi0260132 · Cited by 199 · see citing works
The substrate repertoire of γ-secretase/presenilin
Güner, G., & Lichtenthaler, S. F. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.05.019 · Cited by 195 · see citing works
The Type 4 Prepilin Peptidases Comprise a Novel Family of Aspartic Acid Proteases
LaPointe, C. F., & Taylor, R. K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.2.1502 · Cited by 192 · see citing works
Recognition of the Amyloid Precursor Protein by Human gamma-secretase
Zhou, R., Yang, G., Guo, X., Zhou, Q., Lei, J., & Shi, Y. (2018) · Worldwide Protein Data Bank · doi:10.2210/pdb6iyc/pdb · Cited by 185 · see citing works
Millhauser, G. L. (1995) · Biochemistry · doi:10.1021/bi00012a001 · Cited by 185 · see citing works
Identification of a novel family of presenilin homologues
Ponting, C. P. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.9.1037 · Cited by 173 · see citing works
Proteomic Profiling of γ-Secretase Substrates and Mapping of Substrate Requirements
Hemming, M. L., Elias, J. E., Gygi, S. P., & Selkoe, D. J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060257 · Cited by 171 · see citing works
Membrane protein folding: how important are hydrogen bonds?
Bowie, J. U. (2010) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2010.10.003 · Cited by 168 · see citing works
Alzheimer disease γ-secretase: a complex story of GxGD-type presenilin proteases
Haass, C., & Steiner, H. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)02394-2 · Cited by 165 · see citing works
Regulated Intramembrane Proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b
Martin, L., Fluhrer, R., Reiß, K., Kremmer, E., Säftig, P., & Haass, C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706661200 · Cited by 155 · see citing works
Self-citationThe TNF–TNFR Family of Co-signal Molecules
So, T., & Ishii, N. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9717-3_3 · Cited by 153 · see citing works
The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER
Stagg, H. R., Thomas, M., van den Boomen, D. J. H., Wiertz, E. J. H. J., Drabkin, H. A., Gemmill, R. M., & Lehner, P. J. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200906110 · Cited by 148 · see citing works
Structure of the Catalytic Pore of γ-Secretase Probed by the Accessibility of Substituted Cysteines
Sato, C., Morohashi, Y., Tomita, T., & Iwatsubo, T. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3614-06.2006 · Cited by 143 · see citing works
A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b
Fluhrer, R., Grammer, G., Israel, L., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1450 · Cited by 138 · see citing works
Self-citationBolduc, D. M., Montagna, D. R., Gu, Y., Selkoe, D. J., & Wolfe, M. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1512952113 · Cited by 138 · see citing works
Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases
Voß, M., Schröder, B., & Fluhrer, R. (2013) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2013.03.033 · Cited by 135 · see citing works
Self-citationProkop, S., Shirotani, K., Edbauer, D., Haass, C., & Steiner, H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m401789200 · Cited by 122 · see citing works
Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u
Chen, C., Malchus, N. S., Hehn, B., Stelzer, W., Avci, D., Langosch, D., & Lemberg, M. K. (2014) · The EMBO Journal · doi:10.15252/embj.201488208 · Cited by 115 · see citing works
Self-citationSato, T., Tang, T.-C., Reubins, G., Fei, J. Z., Fujimoto, T., Kienlen‐Campard, P., Constantinescu, S. N., Octave, J., Aimoto, S., & Smith, S. O. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812261106 · Cited by 111 · see citing works
Xiao, H., Hoerner, J. K., Eyles, S. J., et al. (2005) · Protein Science · doi:10.1110/ps.041001705 · Cited by 106 · see citing works
Friedmann, E., Lemberg, M. K., Weihofen, A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407898200 · Cited by 105 · see citing works
Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics
Langosch, D., Scharnagl, C., Steiner, H., & Lemberg, M. K. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.04.001 · Cited by 104 · see citing works
Self-citationVoß, M., Künzel, U., Higel, F., Kuhn, P., Colombo, A. V., Fukumori, A., Haug‐Kröper, M., Klier, B., Grammer, G., Seidl, A., et al. (2014) · The EMBO Journal · doi:10.15252/embj.201488375 · Cited by 103 · see citing works
Self-citationKuhn, P., Voß, M., Haug‐Kröper, M., et al. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m115.048298 · Cited by 98 · see citing works
Self-citationHsu, F.-F., Yeh, C.-T., Sun, Y.-J., et al. (2014) · Oncogene · doi:10.1038/onc.2014.166 · Cited by 90 · see citing works
Boname, J. M., Bloor, S., Wandel, M. P., Nathan, J. A., Antrobus, R., Dingwell, K. S., Thurston, T. L. M., Smith, D. L., Smith, J. C., Randow, F., et al. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201312009 · Cited by 88 · see citing works
MARCH6 and TRC8 facilitate the quality control of cytosolic and tail‐anchored proteins
Stefanovic-Barrett, S., Dickson, A. S., Burr, S. P., Williamson, J. C., Lobb, I. T., van den Boomen, D. J. H., Lehner, P. J., & Nathan, J. A. (2018) · EMBO Reports · doi:10.15252/embr.201745603 · Cited by 80 · see citing works
Shifting hydrogen bonds may produce flexible transmembrane helices
Cao, Z., & Bowie, J. U. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201298109 · Cited by 72 · see citing works
Novel Class of Polytopic Proteins with Domains Associated with Putative Protease Activity
Grigorenko, A. P., Moliaka, Y., Коровайцева, Г. И., & Rogaev, E. I. (2002) · Biochemistry (Moscow) · doi:10.1023/a:1016365227942 · Cited by 71 · see citing works
Pester, O., Barrett, P. J., Hornburg, D., Hornburg, P., Pröbstle, R., Widmaier, S., Kutzner, C., Dürrbaum, M., Kapurniotu, A., Sanders, C. R., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3112093 · Cited by 70 · see citing works
Self-citationGlycine Perturbs Local and Global Conformational Flexibility of a Transmembrane Helix
Högel, P., Götz, A. A., Kuhne, F., et al. (2018) · Biochemistry · doi:10.1021/acs.biochem.7b01197 · Cited by 65 · see citing works
Self-citationArchaeal signal peptides—A comparative survey at the genome level
Bardy, S. L., Eichler, J., & Jarrell, K. (2003) · Protein Science · doi:10.1110/ps.03148703 · Cited by 64 · see citing works
Substrate Requirements for SPPL2b-dependent Regulated Intramembrane Proteolysis
Martin, L., Fluhrer, R., & Haass, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807485200 · Cited by 60 · see citing works
Self-citationThe life cycle of the low-density lipoprotein receptor
Wijers, M., Kuivenhoven, J. A., & van de Sluis, B. (2015) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000157 · Cited by 54 · see citing works
Nyborg, A. C., Jansen, K. R., Ladd, T. B., Fauq, A. H., & Golde, T. E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405879200 · Cited by 53 · see citing works
Latest emerging functions of SPP/SPPL intramembrane proteases
Mentrup, T., Fluhrer, R., & Schröder, B. (2017) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2017.03.002 · Cited by 43 · see citing works
Self-citationFoamy Virus Envelope Protein Is a Substrate for Signal Peptide Peptidase-like 3 (SPPL3)
Voß, M., Fukumori, A., Kuhn, P., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371369 · Cited by 43 · see citing works
Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis
Mentrup, T., Theodorou, K., Cabrera-Cabrera, F., Helbig, A. O., Happ, K., Gijbels, M. J., Gradtke, A.-C., Rabe, B., Fukumori, A., Steiner, H., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20171438 · Cited by 42 · see citing works
Self-citationTransmembrane Substrate Determinants for γ-Secretase Processing of APP CTFβ
Fernandez, M. A., Biette, K. M., Dolios, G., Seth, D., Wang, R., & Wolfe, M. S. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00718 · Cited by 40 · see citing works
Fluhrer, R., Martin, L., Klier, B., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.328104 · Cited by 40 · see citing works
Self-citationModulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage
Götz, A., Mylonas, N. T., Högel, P., Silber, M., Heinel, H., Menig, S., Vogel, A., Feyrer, H., Huster, D., Luy, B., et al. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.04.030 · Cited by 40 · see citing works
Self-citationSubstrate processing in intramembrane proteolysis by γ-secretase – the role of protein dynamics
Langosch, D., & Steiner, H. (2016) · Biological Chemistry · doi:10.1515/hsz-2016-0269 · Cited by 39 · see citing works
Self-citationFluhrer, R., Fukumori, A., Martin, L., Grammer, G., Haug‐Kröper, M., Klier, B., Winkler, E., Kremmer, E., Condron, M. M., Teplow, D. B., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806092200 · Cited by 38 · see citing works
Self-citationYücel, S. S., Stelzer, W., Lorenzoni, A., Wozny, M., Langosch, D., & Lemberg, M. K. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.057 · Cited by 38 · see citing works
Self-citationResidue-Specific Side-Chain Packing Determines the Backbone Dynamics of Transmembrane Model Helices
Quint, S., Widmaier, S., Minde, D., Hornburg, D., Langosch, D., & Scharnagl, C. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.08.031 · Cited by 37 · see citing works
Self-citationAPLP1 is endoproteolytically cleaved by γ-secretase without previous ectodomain shedding
Schauenburg, L., Liebsch, F., Eravci, M., Mayer, M., Weise, C., & Multhaup, G. (2018) · Scientific Reports · doi:10.1038/s41598-018-19530-8 · Cited by 36 · see citing works
Signal peptide peptidase‐like 2c impairs vesicular transport and cleaves SNARE proteins
Papadopoulou, A. A., Müller, S. A., Mentrup, T., Shmueli, M. D., Niemeyer, J., Haug‐Kröper, M., von Blume, J., Mayerhofer, A., Feederle, R., Schröder, B., et al. (2019) · EMBO Reports · doi:10.15252/embr.201846451 · Cited by 35 · see citing works
Self-citationScharnagl, C., Pester, O., Hornburg, P., et al. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2014.02.013 · Cited by 33 · see citing works
Self-citationPoschner, B. C., Quint, S., Hofmann, M. W., et al. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.12.077 · Cited by 33 · see citing works
A Cell‐Based Assay Reveals Nuclear Translocation of Intracellular Domains Released by SPPL Proteases
Mentrup, T., Häsler, R., Fluhrer, R., Säftig, P., & Schröder, B. (2015) · Traffic · doi:10.1111/tra.12287 · Cited by 30 · see citing works
Self-citationHüttl, S., Helfrich, F., Mentrup, T., Held, S., Fukumori, A., Steiner, H., Säftig, P., Fluhrer, R., & Schröder, B. (2016) · Biochemical Journal · doi:10.1042/bcj20160156 · Cited by 27 · see citing works
Self-citationThe dynamics of γ-secretase and its substrates
Hitzenberger, M., Götz, A., Menig, S., Brunschweiger, B., Zacharias, M., & Scharnagl, C. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.04.008 · Cited by 26 · see citing works
Self-citationGötz, A. A., Högel, P., Silber, M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-41766-1 · Cited by 24 · see citing works
Self-citationγ-Secretase-Regulated Signaling Typified by Notch Signaling in the Immune System
Nagase, H., & Nakayama, K. (2013) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x113089990054 · Cited by 15 · see citing works
Silber, M., Hitzenberger, M., Zacharias, M., & Muhle‐Goll, C. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00640 · Cited by 15 · see citing works
Self-citationGötz, A., & Scharnagl, C. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200077 · Cited by 13 · see citing works
Self-citationErratum To: Signal peptide peptidase‐like 2c impairs vesicular transport and cleaves SNARE proteins
Papadopoulou, A. A., Müller, S. A., Mentrup, T., et al. (2019) · EMBO Reports · doi:10.15252/embr.201948133 · Cited by 12 · see citing works
Stelzer, W., & Langosch, D. (2019) · Biochemistry · doi:10.1021/acs.biochem.9b00505 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
New insights into the genetic etiology of Alzheimer’s disease and related dementias
Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01024-z · Cited by 2,498 · see citing works
- Authors
- Spitz, C., Schlosser, C., Guschtschin-Schmidt, N., Stelzer, W., Menig, S., Götz, A., Haug-Kröper, M., Scharnagl, C., Langosch, D., Muhle-Goll, C., & Fluhrer, R.
- Affiliations
- University of Augsburg (DE)
- Karlsruhe Institute of Technology (DE)
- Technical University of Munich (DE)
- Leibniz Supercomputing Centre (DE)
- Corresponding author
- Fluhrer, Regina
- ORCID
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 23
- Issue
- 12
- Pages
- 101775
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC7689174
- OpenAlex
- W3097208119
- Cited by
- 23
- References
- 81
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 1
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Repository KITopen (Karlsruhe Institute of Technology) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- OPUS (Augsburg University) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DZNE Pub (submittedVersion, cc-by-nc-nd)
- KITopen
- Funders
- Deutsche Forschungsgemeinschaft (254872893/FL 635/2-2, 263531414/FOR 2290)
- Liaoning Medical University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- ectodomain shedding, SPPL2a, TNF-α, proline insertion, membrane protein processing, substrate specificity
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review