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Revision as of 10:01, 16 January 2022

1 Structural highlights
2 Function
3 Disease
4 Relevance

Structural highlights

stands for the of the neurogenic locus notch homolog protein 3 in complex with 20358 Fab. This NRR is made of encoded by the NOTCH3 gene(In this article, we will only focus on one of the two chains). It is composed of (LNRs respectively ,, and ) and a composed by and .^[1]. Full experimental information is available on OCA. For a guided tour on the structure components in complex with 20358 Fab use FirstGlance.

The X-Ray crystallized structure 5CZX was realized and published in the same article (Article reference^[1]) as 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.


Gene	NOTCH3
Sources	Homo Sapiens, Humans
Length	271 amino acids
Theoretical weight	30,1 KDa
Biochemical function	Signaling receptor activity
Biological process	Multicellular organism development
Cellular component	Integral component of membrane
Ligands and Environments	2x , 6x , 10x , 3x Cl-
Resources	FirstGlance, OCA, PDBe, RCSB, PDBsum


Name
Sources	Homo Sapiens, Humans
Length	226 amino acids
Theoretical weight	24,12 KDa

More informations are available on 20358 Fab heavy chain.


Name
Sources	Homo Sapiens, Humans
Length	214 amino acids
Theoretical weight	23,39 KDa

More informations are available on 20358 Fab light chain.

Function

NOTCH family : The NOTCH family encodes transmembrane receptor proteins that are involved in cell fate determination during development. In the drosophila ^[2] adult midgut, intestinal stem cells (ISCs) produce two types of daughter cells, the nutrient-absorbing enterocytes (ECs) and 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 ^[3] 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

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^[1] 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.

Disease

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 T-ALL (T-lineage acute lymphoblastic leukemia). T-ALL is characterized by the uncontrolled proliferation of T-cell 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 Notch pathway.

As an example, the target genes in the pathway of NOTCH3 or other subtypes of the Notch receptors are expressed by a variety of translocation, 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 . 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. , present within the , is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at 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 RPBJ and co-activators of the mastermind-like (MAML) family to form a transcriptional activation complex. ^[4]

mutations act by destabilizing or completely unfolding the , relaxing the interface that protects the site. These mutations associated with the in the 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.^[1] Activating mutations of two different regions of NOTCH1 were present in >50% of 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. ^[1]

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 NOTCH3-selective inhibitory antibodies.^[1] 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.^[5]

Relevance

The Notch signalling pathway regulates cell-to-cell interaction, embryogenesis as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lies in the mutations of the Notch gene that have been identified as a contributing factor to an extensive range of cancers in mammals. These mutations can change the activity of the pathway rendering it capable of causing various diseases depending on the sub-type of the targeted Notch receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role.^[5]

The Notch signalling pathway has been studied comprehensively and various aspects of this pathway are very well known. Despite this, it is essential to study the pathway further, so as to understand the role it plays in cancer development and explore new treatment strategies focusing on the Notch pathway.

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

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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 on [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 (MOR 203580 in the case of 5CZX) 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.

Sandbox Reserved 1657

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Revision as of 10:01, 16 January 2022

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