User:Apolena Zounarová/Sandbox 1

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====Additional Cleavages in Response to Receptor Activation====
====Additional Cleavages in Response to Receptor Activation====
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Binding of Notch1 ligands such as Delta1 or Jagged1 leads to the dissociation of the heterodimer. This structural change reveals S2 site for a cleavage by metalloprotease TNAα-converting enzyme (TACE), a member of a disintegrin and metalloprotease domain (ADAM) family, which then produces a fragment termed as Notch extracellular truncation (NEXT). S2 site is located between A1710 and V1711 in murine Notch1, 13 amino acids from the TM domain <ref>DOI 10.1016/S1097-2765(00)80417-7</ref><ref>DOI 10.1016/S1097-2765(00)80416-5</ref>, which corresponds with positions 1720 and 1721 in human Notch1 <ref>DOI 10.1371/JOURNAL.PONE.0006613</ref>. The mechanism of ligand-induced dissociation can be explained by mechanical force caused by simultaneous endocytosis in the ligand cell. Thus, the events in the ligand cell are important for the Notch signal transduction as well. Since S2 cleavage is a ligand-regulated step, mutations in heterodimerization domain can mimic ligand-bound stage of the receptor and facilitate Notch proteolysis in a similar manner. (Nichols et al., 2007). The cleavage by metalloprotease probably brings the receptor in a conformation similar to that of constitutively active receptors (Brou et al., 2000).
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Binding of Notch1 ligands such as Delta1 or Jagged1 leads to the dissociation of the heterodimer. This structural change reveals S2 site for a cleavage by metalloprotease TNAα-converting enzyme (TACE), a member of a disintegrin and metalloprotease domain (ADAM) family, which then produces a fragment termed as Notch extracellular truncation (NEXT). S2 site is located between A1710 and V1711 in murine Notch1, 13 amino acids from the TM domain <ref>DOI 10.1016/S1097-2765(00)80417-7</ref><ref>DOI 10.1016/S1097-2765(00)80416-5</ref>, which corresponds with positions 1720 and 1721 in human Notch1 <ref>DOI 10.1371/JOURNAL.PONE.0006613</ref>. The mechanism of ligand-induced dissociation can be explained by mechanical force caused by simultaneous endocytosis in the ligand cell. Thus, the events in the ligand cell are important for the Notch signal transduction as well. Since S2 cleavage is a ligand-regulated step, mutations in heterodimerization domain can mimic ligand-bound stage of the receptor and facilitate Notch proteolysis in a similar manner <ref>DOI 10.1083/JCB.200609014</ref>. The cleavage by metalloprotease probably brings the receptor in a conformation similar to that of constitutively active receptors <ref>DOI 10.1016/S1097-2765(00)80417-7</ref>.
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Although the cleavage at S2 site is prominent for the activation of the Notch pathway (Brou et al., 2000), subsequent cleavage by γ-secretase presenilin at S3 site is the one which is responsible for Notch intracellular domain (NICD) production (De Strooper et al., 1999). γ-secretase cleaves between G1743 and V1744 in murine Notch1 (Schroeter et al., 1998), which is G1753 and V1754 in human Notch1 (UniProt ID: P46531 (Bateman et al., 2021)). The same enzymatic activity creates Aβ peptide in Alzheimer‘s disease from β-APP precursor (De Strooper et al., 1999).
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Although the cleavage at S2 site is prominent for the activation of the Notch pathway <ref>DOI 10.1016/S1097-2765(00)80417-7</ref>, subsequent cleavage by γ-secretase presenilin at S3 site is the one which is responsible for Notch intracellular domain (NICD) production <ref>DOI 10.1038/19083</ref>. γ-secretase cleaves between G1743 and V1744 in murine Notch1 <ref>DOI 10.1038/30756</ref>, which is G1753 and V1754 in human Notch1 <ref>DOI 10.1093/NAR/GKAA1100</ref>. The same enzymatic activity creates Aβ peptide in Alzheimer‘s disease from β-APP precursor <ref>DOI 10.1038/19083</ref>.
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== Disease ==
== Disease ==

Revision as of 15:30, 27 April 2022

Notch1 Negative Regulatory Region in T-cell Acute Lymphoblastic Leukaemia

Notch1 Heterodimerization Domain. Juxtamembrane peptide containing the S2 site in green, negative regulatory domain in blue.

Drag the structure with the mouse to rotate

References

  1. ↑ Aster JC, Pear WS, Blacklow SC. Notch signaling in leukemia. Annu Rev Pathol. 2008;3:587-613. doi:, 10.1146/annurev.pathmechdis.3.121806.154300. PMID:18039126 doi:http://dx.doi.org/10.1146/annurev.pathmechdis.3.121806.154300
  2. ↑ Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One. 2009 Aug 24;4(8):e6613. PMID:19701457 doi:10.1371/journal.pone.0006613
  3. ↑ Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One. 2009 Aug 24;4(8):e6613. PMID:19701457 doi:10.1371/journal.pone.0006613
  4. ↑ 10.1093/NAR/GKAA1100
  5. ↑ Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000 Feb;5(2):207-16. doi: 10.1016/s1097-2765(00)80417-7. PMID:10882063 doi:http://dx.doi.org/10.1016/s1097-2765(00)80417-7
  6. ↑ Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell. 2000 Feb;5(2):197-206. doi: 10.1016/s1097-2765(00)80416-5. PMID:10882062 doi:http://dx.doi.org/10.1016/s1097-2765(00)80416-5
  7. ↑ Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS One. 2009 Aug 24;4(8):e6613. PMID:19701457 doi:10.1371/journal.pone.0006613
  8. ↑ Nichols JT, Miyamoto A, Olsen SL, D'Souza B, Yao C, Weinmaster G. DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol. 2007 Feb 12;176(4):445-58. doi: 10.1083/jcb.200609014. PMID:17296795 doi:http://dx.doi.org/10.1083/jcb.200609014
  9. ↑ Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000 Feb;5(2):207-16. doi: 10.1016/s1097-2765(00)80417-7. PMID:10882063 doi:http://dx.doi.org/10.1016/s1097-2765(00)80417-7
  10. ↑ Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell. 2000 Feb;5(2):207-16. doi: 10.1016/s1097-2765(00)80417-7. PMID:10882063 doi:http://dx.doi.org/10.1016/s1097-2765(00)80417-7
  11. ↑ De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518-22. doi: 10.1038/19083. PMID:10206645 doi:http://dx.doi.org/10.1038/19083
  12. ↑ Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998 May 28;393(6683):382-6. doi: 10.1038/30756. PMID:9620803 doi:http://dx.doi.org/10.1038/30756
  13. ↑ . UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 2021 Jan 8;49(D1):D480-D489. doi: 10.1093/nar/gkaa1100. PMID:33237286 doi:http://dx.doi.org/10.1093/nar/gkaa1100
  14. ↑ De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518-22. doi: 10.1038/19083. PMID:10206645 doi:http://dx.doi.org/10.1038/19083
  15. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  16. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644

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