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{{5CZX}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
{{5CZX}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE -->
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==<scene name='86/868190/Nrr_domain_alonecentre/2'>5CZX</scene>==
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==<scene name='86/868190/Surface_representation/1'>5CZX</scene>==
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<StructureSection load='5czx' size='360' side='right' caption='Crystal structure of Notch3 NRR' scene='86/868190/Nrr_domain_alonecentre/2'>
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<StructureSection load='5czx' size='360' side='right' caption='Crystal structure of Notch3 NRR' scene='86/868190/Surface_representation/1'>
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5CZX is the NRR (negative regulatory region) of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene]. It's 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>
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5CZX is the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR (negative regulatory region)</scene> of the [https://www.uniprot.org/uniprot/Q9UM47 neurogenic locus notch homolog protein 3] encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene]. It's 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>
There are 4 [https://en.wikipedia.org/wiki/Notch_signaling_pathway notch receptors] in [https://en.wikipedia.org/wiki/Mammal mammals], all of which are transmembrane proteins and notch signalling regulates a very diverse set of biological functions; The most commun is the [https://en.wikipedia.org/wiki/Cell_lineage#:~:text=Cell%20lineage%20denotes%20the%20developmental,that%20can%20no%20longer%20divide. cell lineage determination]. Therefore, changes in the activity of these receptors is associated with various benign and malignant diseases 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.
There are 4 [https://en.wikipedia.org/wiki/Notch_signaling_pathway notch receptors] in [https://en.wikipedia.org/wiki/Mammal mammals], all of which are transmembrane proteins and notch signalling regulates a very diverse set of biological functions; The most commun is the [https://en.wikipedia.org/wiki/Cell_lineage#:~:text=Cell%20lineage%20denotes%20the%20developmental,that%20can%20no%20longer%20divide. cell lineage determination]. Therefore, changes in the activity of these receptors is associated with various benign and malignant diseases 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.
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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 (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 RBPJ 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 (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 RBPJ 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>
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NRR mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<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> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" />
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<scene name='86/868190/Nrr_domain_alonecentre/2'>NRR</scene> mutations act by destabilizing or completely unfolding the <scene name='86/868190/Hd/1'>HD domain</scene>, relaxing the interface that protects the <scene name='86/868190/S2_domaintrue/5'>S2</scene> site. These mutations associated with the <scene name='86/868190/Hd/1'>HD domain</scene> in the <scene name='86/868190/Nrr_domain_alonecentre/2'>NRR domain</scene> lead to increased Notch signaling by way increased expression of the target gene that leads to abnormal levels of the ICD of Notch. These abnormally high levels of ICD of the Notch receptors are understood to be the cause of the development of several different human cancers.<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> Activating mutations of two different regions of [https://en.wikipedia.org/wiki/Notch_1 NOTCH1] were present in >50% of [https://science.sciencemag.org/content/306/5694/269 T-cell acute lymphoblastic leukemia (T-ALL)]. Abnormally high amounts of NOTCH3 were reported to be in approximately 10–25% of ovarian adenocarcinomas. NOTCH3 mutations have also been reported in around 1% of head and neck squamous carcinomas, ovarian cancers, and lung adenocarcinoma. <ref name="oncogene" />
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on [https://www.nature.com/articles/onc2016133#Abs1 NOTCH3-selective inhibitory antibodies].<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref>
Further research on the NOTCH3 activation is key to providing a way forward to identify the different human cancers that could potentially respond to therapy based on [https://www.nature.com/articles/onc2016133#Abs1 NOTCH3-selective inhibitory antibodies].<ref name="oncogene" /> Furthermore, the development of well-characterized diagnostic reagents and biomarkers tests related to the ''Notch'' pathway is essential to fully deciphering the complex role of ''Notch'' receptors in cancer, thereby promoting more successful trials of similar ''Notch'' pathway inhibitors as a plausible treatment for cancer patients.<ref name="roles">doi:10.1146/annurev-pathol-052016-100127</ref>

Revision as of 21:37, 18 January 2021

Template:5CZX

Crystal structure of Notch3 NRR

Drag the structure with the mouse to rotate

References

  1. ↑ 1.0 1.1 1.2 1.3 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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. ↑ 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
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