Sandbox Reserved 1657
From Proteopedia
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<scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene> stands for the <scene name='86/868190/Nrr_domain_alonecentre/4'>NRR (negative regulatory region)</scene> of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] in complex with 20358 [https://en.wikipedia.org/wiki/Fragment_antigen-binding Fab]. This NRR is made of <scene name='86/868190/4zlp_2_chains_nrr/1'>2 identical chain structures</scene> encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene](In this article, we will only focus on one of the two chains). It is composed of <scene name='86/868190/Lnr_domains/1'>three LIN12/Notch repeats and linker</scene> (LNRs respectively <scene name='86/868190/Lna_domain/1'>LNR-A</scene>,<scene name='86/868190/Lnb_domain/1'>LNR-B</scene>, <scene name='86/868190/Lrn_linker_bc/1'>LNR-B/C linker</scene> and <scene name='86/868190/Lnc/1'>LNR-C</scene> ) and a <scene name='86/868190/Hd/1'>heterodimerization domain (HD)</scene> composed by <scene name='86/868190/Hd-c/1'>HD-C</scene> and <scene name='86/868190/Hd-n/1'>HD-N</scene>.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA]. For a guided tour on the structure components in complex with [https://swissmodel.expasy.org/templates/5czx.2 20358 Fab] use [https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance]. | <scene name='86/868190/5czx_version_2_with_ligands/1'>5CZX</scene> stands for the <scene name='86/868190/Nrr_domain_alonecentre/4'>NRR (negative regulatory region)</scene> of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] in complex with 20358 [https://en.wikipedia.org/wiki/Fragment_antigen-binding Fab]. This NRR is made of <scene name='86/868190/4zlp_2_chains_nrr/1'>2 identical chain structures</scene> encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene](In this article, we will only focus on one of the two chains). It is composed of <scene name='86/868190/Lnr_domains/1'>three LIN12/Notch repeats and linker</scene> (LNRs respectively <scene name='86/868190/Lna_domain/1'>LNR-A</scene>,<scene name='86/868190/Lnb_domain/1'>LNR-B</scene>, <scene name='86/868190/Lrn_linker_bc/1'>LNR-B/C linker</scene> and <scene name='86/868190/Lnc/1'>LNR-C</scene> ) and a <scene name='86/868190/Hd/1'>heterodimerization domain (HD)</scene> composed by <scene name='86/868190/Hd-c/1'>HD-C</scene> and <scene name='86/868190/Hd-n/1'>HD-N</scene>.<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5czx OCA]. For a guided tour on the structure components in complex with [https://swissmodel.expasy.org/templates/5czx.2 20358 Fab] use [https://proteopedia.org/wiki/fgij/fg.htm?mol=5CZX FirstGlance]. | ||
| - | The X-Ray crystallized structure 5CZX was realized and published in the same article (Article reference<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>) as [https://www.rcsb.org/structure/5CZV 5CZV] (Notch 3 NRR in complex with 20350) in order to exhibit the areas of the NRR bound by the studied antibody and draw conclusions regarding their Notch3 signalling inhibitory properties | + | The X-Ray crystallized structure 5CZX was realized and published in the same article (Article reference<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref>) as [https://www.rcsb.org/structure/5CZV 5CZV] (Notch 3 NRR in complex with 20350) in order to exhibit the areas of the NRR bound by the studied antibody (MOR 203580 in the case of 5CZX) and draw conclusions regarding their Notch3 signalling inhibitory properties. |
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<table><tr><td colspan='3'><br> | <table><tr><td colspan='3'><br> | ||
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== Function == | == Function == | ||
| - | '''[https:// | + | '''[https://en.wikipedia.org/wiki/Notch_proteins NOTCH family] :''' The NOTCH family encodes [https://en.wikipedia.org/wiki/Cell_surface_receptor transmembrane receptor proteins] that are involved in cell fate determination during development. In the drosophila <ref name=Drosophila >DOI:10.1126/science.aab0988</ref> adult midgut, intestinal [https://en.wikipedia.org/wiki/Stem_cell stem cells] (ISCs) produce two types of daughter cells, the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837124/#:~:text=Enterocytes%20are%20specialized%20to%20absorb,along%20the%20crypt%2Dvillus%20axis. nutrient-absorbing enterocytes (ECs)] and [https://en.wikipedia.org/wiki/Enteroendocrine_cell secretory enteroendocrine cells]. Notch signalling between intestinal stem cells and their daughter cells guides cell specification. ISCs with elevated levels of the Notch Delta ligand more primarily activate the Notch signalling pathway in daughter cells and cause them to become ECs. However, ISCs having low levels of Notch Delta ligand direct daughter cells to become enteroendocrine cells. |
The NOTCH gene family in humans <ref name=Function>DOI:10.1038/sj.onc.1203276</ref> has a link with the Drosophila Notch gene. Members of the NOTCH gene family encode transmembrane receptor proteins that are useful to determine the cell fate during development. | The NOTCH gene family in humans <ref name=Function>DOI:10.1038/sj.onc.1203276</ref> has a link with the Drosophila Notch gene. Members of the NOTCH gene family encode transmembrane receptor proteins that are useful to determine the cell fate during development. | ||
| - | ''' | + | '''Notch3 NRR :''' receives a signal and transmits it in the cell to initiate a change in cell activity.It can also used in the neuron fate commitment, artery morphogenesis or the regulation of NOTCH signaling pathway |
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| + | '''MOR 20358 :''' an Anti-Human Notch 3 recombinant antibody designed for therapeutic purpose in the curing of the T-Cell Acute lymphoblastic leukemia disease. | ||
| + | The study<ref name="oncogene">Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133</ref> for which it was designed has provided evidence that MOR 20358 binds to half of the LRN-C linker and parts of the HD-C and the LNR-B/C domains, which would therefore lock the Notch 3 NRR in an auto-inhibitory conformation, ending up inhibiting the Notch signalling. This property may constitute a treatment in cases of Notch3 over-activation related cancers. | ||
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== Disease == | == Disease == | ||
| - | It is well understood that the | + | It is well understood that the Notch receptors plays an important role in cancer development in mammals and changes the activity of these receptors which dysfunction can be associated with various benign and malignant diseases such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142501/ T-ALL (T-lineage acute lymphoblastic leukemia)]. T-ALL is characterized by the uncontrolled proliferation of T-cell [https://en.wikipedia.org/wiki/Lymphoblast lymphoblasts] in the blood, the brown marrow and the tissues. These oncogenic mechanisms of the ''Notch'' receptors are dependant on its intracelluclar signaling. Therefore, in order to understand how the cancer develops due to these receptors, it is necessary to understand the [https://en.wikipedia.org/wiki/Notch_signaling_pathway Notch pathway]. |
As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. <scene name='86/868190/S2_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a disintegrin and metalloprotease ([https://en.wikipedia.org/wiki/ADAM_(protein) ADAM]). Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor [https://www.uniprot.org/uniprot/Q06330 RPBJ] and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref> | As an example, the target genes in the pathway of [https://en.wikipedia.org/wiki/Notch_3 NOTCH3] or other subtypes of the ''Notch'' receptors are expressed by a variety of translocation, [https://en.wikipedia.org/wiki/Post-translational_modification post-translational modifications] and activation of ligands associated to it. Following translation, Furin-like convertase modifies the ''Notch'' receptor by proteolytic cleavage at site 1 (S1) and transported to the cell surface held together by the <scene name='86/868190/Hd/1'>heterodimerization (HD) domain</scene>. The ''Notch'' receptor on the signal‐receiving cell binds to a ligand on the cell surface of a neighboring signal‐sending cell, causing it to get activated. This binding causes a change in the conformation of the receptor. <scene name='86/868190/S2_domaintrue/5'>Site 2</scene>, present within the <scene name='86/868190/Nrr_domain_alonecentre/2'>negative regulatory region (NRR) domain</scene>, is thus exposed for cleavage by a disintegrin and metalloprotease ([https://en.wikipedia.org/wiki/ADAM_(protein) ADAM]). Notch cleavage at <scene name='86/868190/S2_domaintrue/5'>S2</scene> generates the membrane‐anchored Notch extracellular truncation (NEXT) fragment, a substrate for the γ‐secretase complex. Thus, the ''Notch'' receptor is cleaved by the γ-secretase complex. Following γ-secretase cleavage, the intracellular domain (ICD) of NOTCH3 translocates to the nucleus where it interacts with the DNA-binding factor [https://www.uniprot.org/uniprot/Q06330 RPBJ] and co-activators of the [https://en.wikipedia.org/wiki/MAML1 mastermind-like (MAML)] family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref> | ||
Revision as of 22:10, 15 January 2022
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References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Bernasconi-Elias, P., Hu, T., Jenkins, D. et al. Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35, 6077–6086 (2016). https://doi.org/10.1038/onc.2016.133
- ↑ Guo Z, Ohlstein B. Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science. 2015 Nov 20;350(6263). pii: 350/6263/aab0988. doi:, 10.1126/science.aab0988. PMID:26586765 doi:http://dx.doi.org/10.1126/science.aab0988
- ↑ Callahan R, Smith GH. MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene. 2000 Feb 21;19(8):992-1001. doi: 10.1038/sj.onc.1203276. PMID:10713682 doi:http://dx.doi.org/10.1038/sj.onc.1203276
- ↑ Aburjania Z, Jang S, Whitt J, Jaskula-Stzul R, Chen H, Rose JB. The Role of Notch3 in Cancer. Oncologist. 2018 Aug;23(8):900-911. doi: 10.1634/theoncologist.2017-0677. Epub, 2018 Apr 5. PMID:29622701 doi:http://dx.doi.org/10.1634/theoncologist.2017-0677
- ↑ 5.0 5.1 Aster JC, Pear WS, Blacklow SC. The Varied Roles of Notch in Cancer. Annu Rev Pathol. 2017 Jan 24;12:245-275. doi:, 10.1146/annurev-pathol-052016-100127. Epub 2016 Dec 5. PMID:27959635 doi:http://dx.doi.org/10.1146/annurev-pathol-052016-100127
