Sandbox Reserved 1701: Difference between revisions

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MRGPRX2 is a certain type of [https://proteopedia.org/wiki/index.php/G_protein-coupled_receptor GPCR] that is located in the cellular membranes of mast cells.

[[Image:Main_figure.png|425px|right|thumb|'''Figure 1.''' MRGPRX2 as it sits within the cellular membrane. Phospholipid bilayer is represented by grey dots, with labeled cellular locations]]

[[Image:Main_figure.png|425px|right|thumb|'''Figure 1.''' MRGPRX2 as it sits within the cellular membrane. Phospholipid bilayer is represented by grey dots, with labeled cellular locations. PDB: 7s8l]]

== Background ==

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[https://proteopedia.org/wiki/index.php/G_protein GTP-binding proteins], also known as G-proteins, are heterotrimeric complexes consisting of <scene name=''90/904305/Structure_overview_alpha/2'>alpha</scene>, <scene name='90/904305/Structure_overview_beta/2'>beta</scene>, and <scene name='90/904305/Structure_overview_gamma/2'>gamma</scene> subunits that interact with the intracellular transmembrane region at an <scene name='90/904306/Interface_2/1'>interface</scene> ( '''Figure 2b'''). G-proteins are responsible for [https://en.wikipedia.org/wiki/Signal_transduction transmitting] extracellular signals into the cell upon activation. Activation leads to a substitution of GDP with GTP within the alpha subunit, causing the alpha subunit to disassociate from the beta and gamma subunits to initiate an intracellular signaling cascade. There are different families of G-alpha subunits, Gαi, Gαs, Gα12/13, and Gαq <ref name="Kamato">PMID: 26664886</ref>. MRGPRX2 binds to both Gαi and Gαq subunits with nearly identical structures despite slightly different amino acids present ( '''Figure 2a''') <ref name= "Cao" /> <ref name= "Yang" />. Throughout this page, MGPRX2 is always shown with Gq. The major difference between the Gq and Gi bound structures comes from one amino acid difference (valine on Gq versus phenylalanine on Gi) that pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein.

[[Image:Gq and gi overlay.png|500px|center|thumb|'''Figure 2a.''' Overlay of MGPRX2-Gq (red-dark blue) and MGPRX2-Gi (cyan-yellow). '''Figure 2b.''' Important residues involved in the interface between MGPRX2 and Gq/ Gi subunits. Arrow pointing to the major difference between the interfaces, which comes from the final C-terminus residue on the G-alpha subunit. In Gq, there is a valine while in Gi, there is a phenylalanine. This pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein. All other interactions are nearly identical.]]

[[Image:Gq and gi overlay.png|500px|center|thumb|'''Figure 2a.''' Overlay of MGPRX2-Gq (red-dark blue) and MGPRX2-Gi (cyan-yellow). '''Figure 2b.''' Important residues involved in the interface between MGPRX2 and Gq/ Gi subunits. Arrow pointing to the major difference between the interfaces, which comes from the final C-terminus residue on the G-alpha subunit. In Gq, there is a valine while in Gi, there is a phenylalanine. This pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein. All other interactions are nearly identical. PDBs: (MRGPRX2-Gq):7s8l and (MRGPRX2-Gi):7s8m]]

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== Function ==

[[Image:Screen Shot 2022-04-162 at 2.49.26 PM.png|420px|right|thumb|'''Figure 8.'''Schematic representation of cellular response]]

GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] (~~figure~~ 8)<ref name="Porebski">PMID: 30619367</ref>.

GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] ('''Figure 8''')<ref name="Porebski">PMID: 30619367</ref>.

=== Before Activation ===

The culmination of different motifs observed in MRGPRX2 compared to other class A GPCRs leads to external membrane ligand binding. The MRGPRX2 GPCR undergoes a much smaller conformational change upon ligand binding compared to other Class A GPCRs due to surface level binding versus deep helix binding ('''Figure 9'''). This smaller change can be seen as only minor extracellular movement occurs in MRGRPX2 upon binding compared to other GPCRs which can undergo loop and helical conformational changes<ref name="Hoffmann">PMID: 18059316</ref>.

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=== After Activation ===

After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files 1bof and 1cip.

After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files [https://www.rcsb.org/structure/1BOF 1bof] and [https://www.rcsb.org/structure/1CIP 1cip].

[[Image:Screen Shot 2022-03-282 at 6.59.44 PM.png|500px|center|thumb|'''Figure 9.''' Overlay of unbound (transparent) and bound (opaque) transmembrane proteins of both MRGRPX2 (left) and 5-HT2AR (right). PDBs: (MRGPRX2): 7s8l and (5HT2A): 6wha.]]

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@@ Line 4: / Line 4: @@
 MRGPRX2 is a certain type of [https://proteopedia.org/wiki/index.php/G_protein-coupled_receptor GPCR] that is located in the cellular membranes of mast cells.
-[[Image:Main_figure.png|425px|right|thumb|'''Figure 1.''' MRGPRX2 as it sits within the cellular membrane. Phospholipid bilayer is represented by grey dots, with labeled cellular locations]]
+[[Image:Main_figure.png|425px|right|thumb|'''Figure 1.''' MRGPRX2 as it sits within the cellular membrane. Phospholipid bilayer is represented by grey dots, with labeled cellular locations. PDB: 7s8l]]
 == Background ==
@@ Line 27: / Line 27: @@
 [https://proteopedia.org/wiki/index.php/G_protein GTP-binding proteins], also known as G-proteins, are heterotrimeric complexes consisting of <scene name=''90/904305/Structure_overview_alpha/2'>alpha</scene>, <scene name='90/904305/Structure_overview_beta/2'>beta</scene>, and <scene name='90/904305/Structure_overview_gamma/2'>gamma</scene> subunits that interact with the intracellular transmembrane region at an  <scene name='90/904306/Interface_2/1'>interface</scene> ( '''Figure 2b'''). G-proteins are responsible for [https://en.wikipedia.org/wiki/Signal_transduction transmitting] extracellular signals into the cell upon activation. Activation leads to a substitution of GDP with GTP within the alpha subunit, causing the alpha subunit to disassociate from the beta and gamma subunits to initiate an intracellular signaling cascade.  There are different families of G-alpha subunits, Gαi, Gαs, Gα12/13, and Gαq <ref name="Kamato">PMID: 26664886</ref>. MRGPRX2 binds to both Gαi and Gαq subunits with nearly identical structures despite slightly different amino acids present ( '''Figure 2a''') <ref name= "Cao" /> <ref name= "Yang" />. Throughout this page, MGPRX2 is always shown with Gq. The major difference between the Gq and Gi bound structures comes from one amino acid difference (valine on Gq versus phenylalanine on Gi) that pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein.
-[[Image:Gq and gi overlay.png|500px|center|thumb|'''Figure 2a.''' Overlay of MGPRX2-Gq (red-dark blue) and MGPRX2-Gi (cyan-yellow). '''Figure 2b.''' Important residues involved in the interface between MGPRX2 and Gq/ Gi subunits. Arrow pointing to the major difference between the interfaces, which comes from the final C-terminus residue on the G-alpha subunit. In Gq, there is a valine while in Gi, there is a phenylalanine. This pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein. All other interactions are nearly identical.]]
+[[Image:Gq and gi overlay.png|500px|center|thumb|'''Figure 2a.''' Overlay of MGPRX2-Gq (red-dark blue) and MGPRX2-Gi (cyan-yellow). '''Figure 2b.''' Important residues involved in the interface between MGPRX2 and Gq/ Gi subunits. Arrow pointing to the major difference between the interfaces, which comes from the final C-terminus residue on the G-alpha subunit. In Gq, there is a valine while in Gi, there is a phenylalanine. This pushes the Gi subunit 2Å away from the arginine residue on helix 6 of the transmembrane protein. All other interactions are nearly identical. PDBs: (MRGPRX2-Gq):7s8l and (MRGPRX2-Gi):7s8m]]
@@ Line 98: / Line 98: @@
 == Function ==
 [[Image:Screen Shot 2022-04-162 at 2.49.26 PM.png|420px|right|thumb|'''Figure 8.'''Schematic representation of cellular response]]
-GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] (figure 8)<ref name="Porebski">PMID: 30619367</ref>.
+GPCRs undergo a conformational change in their 7TMD region upon ligand binding. This signal is then transduced to the G-protein allowing for downstream responses due to <scene name='90/904306/Interface_2/1'>interactions</scene> between the alpha subunit of the G-protein and the transmembrane protein which activates g-protein by GTP exchange. This downstream response may be in the form of release of small granules which can be received by a receptor to initiate a [https://proteopedia.org/wiki/index.php/Neurotransmitters#Serotonin_receptors%20Serotonin%20receptors pathological response] ('''Figure 8''')<ref name="Porebski">PMID: 30619367</ref>.
 === Before Activation ===
 The culmination of different motifs observed in MRGPRX2 compared to other class A GPCRs leads to external membrane ligand binding. The MRGPRX2 GPCR undergoes a much smaller conformational change upon ligand binding compared to other Class A GPCRs due to surface level binding versus deep helix binding ('''Figure 9'''). This smaller change can be seen as only minor extracellular movement occurs in MRGRPX2 upon binding compared to other GPCRs which can undergo loop and helical conformational changes<ref name="Hoffmann">PMID: 18059316</ref>.
@@ Line 104: / Line 104: @@
 === After Activation ===
-After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files 1bof and 1cip.
+After ligand binding and transmembrane protein activation, this signal is transmitted to the alpha subunit of the G-protein which undergoes chemical and conformational changes. The alpha subunit is initially bound with GDP which is then physically replaced by GTP leading to conformational changes. These changes can be seen in this [https://youtu.be/k4fjSZV_-OQ video] of a G-protein alpha subunit activation derived from common rats. This video was constructed by one of the page's authors using PDB files [https://www.rcsb.org/structure/1BOF 1bof] and [https://www.rcsb.org/structure/1CIP 1cip].
 [[Image:Screen Shot 2022-03-282 at 6.59.44 PM.png|500px|center|thumb|'''Figure 9.''' Overlay of unbound (transparent) and bound (opaque) transmembrane proteins of both MRGRPX2 (left) and 5-HT2AR (right). PDBs: (MRGPRX2): 7s8l and (5HT2A): 6wha.]]