Proteopedia - User contributions [en]

Sandbox Reserved 1657

2021-01-14T20:29:10Z

Sanika Kulkarni:

<scene name='86/868190/Test_1/2'>Text To Be Displayed</scene>{{5CZX}}
==5CZX==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>

The neurogenic locus notch homolog protein 3 is a protein encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene]. 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.

== Function ==
'''[https://www.creative-diagnostics.com/notch-family.htm 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 (ee) 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 ee 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.

'''5CZX :''' 5CZX 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
== Disease ==

It is well understood that the [https://en.wikipedia.org/wiki/Notch_proteins Notch] receptors play an important role in cancer development in mammals. 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 heterodimerization (HD) domain. 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. Site 2 (S2), present within the negative regulatory region (NRR) domain, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at S2 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>

NRR mutations act by destabilizing or completely unfolding the HD domain, relaxing the interface that protects the S2 site. These mutations associated with the HD domain in the NRR domain 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>

== Relevance ==

The ''Notch'' signaling pathway regulates cell-cell interaction, [https://en.wikipedia.org/wiki/Embryonic_development embryogenesis] as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lie in the mutations in the ''Notch'' gene that have been identified in an extensive range of cancers in mammals. These mutations can change the activity of the pathway rendering it capable of causing [https://pubmed.ncbi.nlm.nih.gov/22306179/ various diseases] depending on the sub-type of the ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role.<ref name="roles" />

The ''Notch'' signaling 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 novel treatment strategies focusing on the ''Notch'' pathway.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1657

2021-01-14T19:25:39Z

Sanika Kulkarni:

{{5CZX}}
==5CZX==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
The neurogenic locus notch homolog protein 3 is a protein encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene]. 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.

== Function ==
'''[https://www.creative-diagnostics.com/notch-family.htm 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 (ee) 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 ee 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.

'''5CZX :''' 5CZX 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
== Disease ==

It is understood that the Notch receptors play an important role in cancer development in mammals. 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
The target genes in the Notch pathway 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 heterodimerization (HD) domain. 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. Site 2 (S2), present within the negative regulatory region (NRR) domain, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at S2 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 Notch translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the mastermind-like (MAML) family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref>

NRR mutations act by destabilizing or completely unfolding the HD domain, relaxing the interface that protects the S2 site. These mutations associated with the HD domain in the NRR domain 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 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. <ref name="oncogene" />

== Relevance ==

The ''Notch'' signaling pathway regulates cell-cell interaction, embryogenesis as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lie in the mutations in the ''Notch'' gene that have been identified in 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 ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role. <ref>doi:10.1146/annurev-pathol-052016-100127</ref>

The ''Notch'' signaling 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 novel treatment strategies focusing on the ''Notch'' pathway.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<scene name="/12/3456/Sample/3">col</scene>

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1657

2021-01-14T19:16:34Z

Sanika Kulkarni:

{{5CZX}}
==5CZX==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
The neurogenic locus notch homolog protein 3 is a protein encoded by the [https://en.wikipedia.org/wiki/Notch_3 NOTCH3 gene]. 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 ymphoblasts] in the blood, the brown marrow and the tissues.

== Function ==
'''[https://www.creative-diagnostics.com/notch-family.htm 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] 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 (ee) 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 ee 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.

'''5CZX :''' 5CZX 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
== Disease ==

It is understood that the Notch receptors play an important role in cancer development in mammals. 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
The target genes in the Notch pathway 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 heterodimerization (HD) domain. 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. Site 2 (S2), present within the negative regulatory region (NRR) domain, is thus exposed for cleavage by a disintegrin and metalloprotease (ADAM). Notch cleavage at S2 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 Notch translocates to the nucleus where it interacts with the DNA-binding factor RBPJ and co-activators of the mastermind-like (MAML) family to form a transcriptional activation complex. <ref>doi:10.1634/theoncologist.2017-0677</ref>

NRR mutations act by destabilizing or completely unfolding the HD domain, relaxing the interface that protects the S2 site. These mutations associated with the HD domain in the NRR domain 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.
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. <ref>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>

== Relevance ==

The ''Notch'' signaling pathway regulates cell-cell interaction, embryogenesis as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lie in the mutations in the ''Notch'' gene that have been identified in 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 ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role. <ref>doi:10.1146/annurev-pathol-052016-100127</ref>

The ''Notch'' signaling 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 novel treatment strategies focusing on the ''Notch'' pathway.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<scene name="/12/3456/Sample/3">col</scene>

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1657

2021-01-14T18:13:07Z

Sanika Kulkarni:

{{5CZX}}
==5CZX==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
The neurogenic locus notch homolog protein 3 is a protein encoded by the NOTCH3 gene. There are 4 notch receptors in mammals, all of which are transmembrane proteins and notch signalling regulates a very diverse set of biological functions; The most commun is the cell lineage determination. Therefore, changes in the activity of these receptors is associated with various benign and malignant diseases 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.

== Function ==
'''NOTCH family :''' The NOTCH family encodes 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 stem
cells produce two types of daughter cells, the nutrient-absorbing enterocytes (ECs) and secretory enteroendocrine (ee) 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 ee 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.

'''5CZX :''' 5CZX 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
== Disease ==

It is understood that the Notch receptors play an important role in cancer development in mammals. 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
The target genes in the Notch pathway 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).
== Relevance ==

The ''Notch'' signaling pathway regulates cell-cell interaction, embryogenesis as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lie in the mutations in the ''Notch'' gene that have been identified in 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 ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role. <ref>doi:10.1146/annurev-pathol-052016-100127</ref>

The ''Notch'' signaling 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 novel treatment strategies focusing on the ''Notch'' pathway.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1657

2021-01-14T17:55:43Z

Sanika Kulkarni:

{{5CZX}}
==5CZX==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
The neurogenic locus notch homolog protein 3 is a protein encoded by the NOTCH3 gene. There are 4 notch receptors in mammals, all of which are transmembrane proteins and notch signalling regulates a very diverse set of biological functions; The most commun is the cell lineage determination. Therefore, changes in the activity of these receptors is associated with various benign and malignant diseases 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.

== Function ==
'''NOTCH family :''' The NOTCH family encodes 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 stem
cells produce two types of daughter cells, the nutrient-absorbing enterocytes (ECs) and secretory enteroendocrine (ee) 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 ee 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.

'''5CZX :''' 5CZX 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
== Disease ==

== Relevance ==

The ''Notch'' signaling pathway regulates cell-cell interaction, embryogenesis as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lie in the mutations in the ''Notch'' gene that have been identified in 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 ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role. <ref>doi:10.1146/annurev-pathol-052016-100127</ref>

The ''Notch'' signaling 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 novel treatment strategies focusing on the ''Notch'' pathway.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1657

2021-01-14T17:46:18Z

Sanika Kulkarni:

{{5CZX}}
==5CZX==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
The neurogenic locus notch homolog protein 3 is a protein encoded by the NOTCH3 gene. There are 4 notch receptors in mammals, all of which are transmembrane proteins and notch signalling regulates a very diverse set of biological functions; The most commun is the cell lineage determination. Therefore, changes in the activity of these receptors is associated with various benign and malignant diseases 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.

== Function ==
'''NOTCH family :''' The NOTCH family encodes 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 stem
cells produce two types of daughter cells, the nutrient-absorbing enterocytes (ECs) and secretory enteroendocrine (ee) 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 ee 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.

'''5CZX :''' 5CZX 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
== Disease ==

== Relevance ==

The ''Notch'' signaling pathway regulates cell-cell interaction, embryogenesis as well as various other biological functions in adult tissues. It is a highly conserved pathway. Its relevance and clinical significance lie in the mutations in the ''Notch'' gene that have been identified in 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 ''Notch'' receptor and more importantly, causing it to play an oncogenic or tumor-suppressive role. <ref>doi:10.1146/annurev-pathol-052016-100127</ref>
The ''Notch'' signaling 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 novel treatment strategies focusing on the ''Notch'' pathway.

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1109

2020-01-17T15:59:25Z

Sanika Kulkarni:

{{Sandbox_ESBS_2019}}
==α-synuclein==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans<ref>DOI 10.1016/j.neuron.2013.09.004</ref>.

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release <ref>DOI 10.1101/cshperspect.a009399</ref>.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/7'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.<ref>doi: 10.1101/cshperspect.a009399</ref>

</StructureSection>
== References ==

<references/>

<ref>doi: 10.1101/cshperspect.a009399</ref>

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Sanika Kulkarni:

{{Sandbox_ESBS_2019}}
==α-synuclein==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans.

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/7'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

</StructureSection>
== References ==

<references/>

Sandbox Reserved 1109

2020-01-17T15:40:56Z

Sanika Kulkarni: Undo revision 3144183 by Sanika Kulkarni (Talk)

{{Sandbox_ESBS_2019}}
==Generalities==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. <ref>DOI 10.1016</ref>

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/7'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

</StructureSection>
== References ==

<references/>

Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/

Sandbox Reserved 1109

2020-01-17T15:36:34Z

Sanika Kulkarni:

{{Sandbox_ESBS_2019}}
==Generalities==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. <ref> DOI 10.1016 <ref>

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/6'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

</StructureSection>
== References ==
Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/
Cold Spring Harb Perspect Med 2012;4:a009399, Stefanis L.a-Synuclein in Parkinson’s Disease .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/pdf/cshperspectmed-PKD-a009399.pdf
UniProtKB - P37840 (SYUA_HUMAN) https://www.uniprot.org/uniprot/P37840

<references/>

Sandbox Reserved 1109

2020-01-17T15:36:24Z

Sanika Kulkarni:

{{Sandbox_ESBS_2019}}
==Generalities==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. <ref> DOI 10.1016 <ref>

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/7'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

</StructureSection>
== References ==
Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/
Cold Spring Harb Perspect Med 2012;4:a009399, Stefanis L.a-Synuclein in Parkinson’s Disease .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/pdf/cshperspectmed-PKD-a009399.pdf
UniProtKB - P37840 (SYUA_HUMAN) https://www.uniprot.org/uniprot/P37840

<references/>

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{{Sandbox_ESBS_2019}}
==Generalities==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. </ref>

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/6'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

</StructureSection>
== References ==
<ref> Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/
Cold Spring Harb Perspect Med 2012;4:a009399, Stefanis L.a-Synuclein in Parkinson’s Disease .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/pdf/cshperspectmed-PKD-a009399.pdf
UniProtKB - P37840 (SYUA_HUMAN) https://www.uniprot.org/uniprot/P37840

<references/>

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Sanika Kulkarni:

{{Sandbox_ESBS_2019}}
==Generalities==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>

α-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. α-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of the total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. </11>

== Function ==

Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately but progresses with time. Excessive expression of α-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving α-synuclein a chaperone-like function where this protein works with the CSPα in the assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the α-synuclein is to regulate the neurotransmitter release.

== Structure ==

The <scene name='82/829362/Default_scene/4'>alpha-synuclein (1-121)</scene> is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 <scene name='82/829362/beta-strands/6'>beta-strands interrupted by glycines</scene>, between the residues 42 to about 102 forming the ꞵ-arch <ref>DOI 10.7554/eLife.36402</ref>. These glycines help the folding of the molecule by their small size. The ꞵ-arch is stabilized by <scene name='82/829362/Hydrogen_bond/1'>hydrogen bonds N65-G68 and Q79-G86</scene>.

Two structures coincide thanks to the presence of <scene name='82/829362/Hydrophobic/3'>hydrophobic (red) and hydrophilic(blue) regions</scene>. A hydrophobic intra-molecular core between the two protofilaments is formed by <scene name='82/829362/Hydrophobic_ala_val_ile/3'>alanines, valines and one isoleucine</scene><ref>DOI 10.7554/eLife.36402</ref>. Residues from 54 to 75 form a <scene name='82/829362/Hydrophilic_channel/5'>hydrophilic channel</scene> which contains majority of threonines and glutamic acid<ref>DOI 10.7554/eLife.36402</ref>. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: <scene name='82/829362/Hydrophobic_glu_lys/2'>Lysine and glutamic acid</scene>.

Fibrils form by stacking a <scene name='82/829362/Rod_polymorph/1'>rod polymorph</scene>. It is a helix with a pitch of 920 Å<ref>DOI 10.1038/s41467-018-05971-2</ref>.

== Disease ==
Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide <ref>(https://www.parkinson.org/Understanding-Parkinsons/Statistics)</ref>. One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.<ref>https://doi.org/10.1038/35081564</ref>.
==Mechanism of aggregation==

Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease <ref>PMID: 9546347</ref>. Lewy Bodies are cytoplasmic inclusion made of primarily α-synuclein protein, and may also contain other proteins such as; ubiquitin, Tau proteins. The structure of α-synuclein; N-terminal domain, C-terminal domain, and a hydrophobic core (NAC) suggests an aggregation pathway due to the unfolded nature of the protein. A recent study published by the in Science Translational Medicine Journal, suggests that a covalent modification such as Serine-129 phosphorylation in α-synuclein, as well as hydrophobic interactions specifically located at the NAC domain of α-synuclein, allows for the polymerization of different α-synuclein protein into an anti-parallel β-sheet conformation permitting the formation of fibrils. The role of α-synuclein in the pathogenesis of PD is mediated through the formation of the 58-83 KD complex that contains α-synuclein and 14-3-3 protein, which inhibits BCL-BAD protein complex responsible for the inhibition of Apoptosis. However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD).<ref>doi: 10.1126/scitranslmed.3002566</ref>
== Relevance ==

Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the α-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the α-synuclein is not totally understood. α-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

</StructureSection>
== References ==
<11> Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/
Cold Spring Harb Perspect Med 2012;4:a009399, Stefanis L.a-Synuclein in Parkinson’s Disease .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/pdf/cshperspectmed-PKD-a009399.pdf
UniProtKB - P37840 (SYUA_HUMAN) https://www.uniprot.org/uniprot/P37840

<references/>

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{{Sandbox_ESBS_2019}}
==Generalities==
<StructureSection load='6flt' size='340' side='right'caption='[[6flt]], [[Resolution|resolution]] 3.42Å' scene=''>
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Function ==

== Structure ==

The alpha-synuclein (1-121) (default scene) is about 14 kDa fibril constituted by two protofilaments of 121 residues <ref>DOI 10.7554/eLife.36402</ref>. The presence of many ꞵ-sheet induce a Greek-key motif of 99Å diameter <ref>DOI 10.1038/s41467-018-05971-2</ref>. Indeed, There are 8 Beta-strands interrupted by glycines <scene name='82/829362/Beta-strands/1'>TextToBeDisplayed</scene>, between the residues 42 to about 102 <ref>DOI 10.7554/eLife.36402</ref>.
Two structures coincide thanks to the presence of hydrophobic and hydrophilic regions. A hydrophobic intra-molecular core between the two protofilaments is formed by alanines, valines and one isoleucine. A hydrophilic channel contains majority of threonines. To stabilize the protein in an aqueous solution, there are solvent exposed charged residues : Lysine and glutamic acid.

== Disease ==
One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, two main hypotheses have been developed surrounding Parkinson's disease research. Firstly, the missense mutation of the α-synuclein gene is a rare genetic disorder that cause Parkinson's disease. Secondly, the α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases.
== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>