Sandbox Ben Whiteside: Difference between revisions
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RAMPs are accessory proteins required for the appropriate localization and function of GPCRs <ref name="Parameswaran">PMID:17010614</ref>. As of now, there are three notable roles of RAMPs. RAMPs can allow for the signaling and trafficking of GPCRs from the endoplasmic reticulum to the cell membrane. Additionally, RAMPs are known to alter the interactions between the receptor and ligands, potentially inhibiting or activating the receptor. Lastly, RAMPs are also thought to play a role in the internalization and subsequent inactivation of GPCRs, by signaling receptor fate and recycling from the cell membrane <ref name="Hay"/>. In the case of the AMYR, the RAMP acts as a scaffold to hold the transmembrane domain in place. More importantly, the RAMP restricts the dynamic movement of the extracellular domain of the calcitonin receptor, anchoring the CTR into the membrane. | RAMPs are accessory proteins required for the appropriate localization and function of GPCRs <ref name="Parameswaran">PMID:17010614</ref>. As of now, there are three notable roles of RAMPs. RAMPs can allow for the signaling and trafficking of GPCRs from the endoplasmic reticulum to the cell membrane. Additionally, RAMPs are known to alter the interactions between the receptor and ligands, potentially inhibiting or activating the receptor. Lastly, RAMPs are also thought to play a role in the internalization and subsequent inactivation of GPCRs, by signaling receptor fate and recycling from the cell membrane <ref name="Hay"/>. In the case of the AMYR, the RAMP acts as a scaffold to hold the transmembrane domain in place. More importantly, the RAMP restricts the dynamic movement of the extracellular domain of the calcitonin receptor, anchoring the CTR into the membrane. | ||
==Structure== | ==Structure== | ||
==== G-alpha Interactions with CTR TMD ==== | ==== G-alpha Interactions with CTR TMD ==== | ||
To transduce the signal across the cell membrane, the binding of amylin will induce a conformational change that allows for the CTR to make favorable interactions with the G alpha subunit. Two interactions shown <scene name='10/1038828/Ctr_g_alpha/15'>(1, </scene><scene name='10/1038828/Ctr_g_alpha/12'>2) </scene> activate the G-protein and propel downstream signaling. As with a typical glucagon GPCR pathway, the G-alpha subunit becomes activated upon guanine exchange factor [https://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factor (GEF)] echanging GDP for GTP. This G-alpha subunit transverses laterally in the membrane towards adenylyl cyclase, activating it and causing an increase in the second messenger cyclic adenosine monophosphate [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate (cAMP)]. This cAMP activates protein kinase A [https://en.wikipedia.org/wiki/Protein_kinase_A (PKA)], which can phosphorylate other proteins facilitating cellular response. | To transduce the signal across the cell membrane, the binding of amylin will induce a conformational change that allows for the CTR to make favorable interactions with the G alpha subunit. Two interactions shown <scene name='10/1038828/Ctr_g_alpha/15'>(1, </scene><scene name='10/1038828/Ctr_g_alpha/12'>2) </scene> activate the G-protein and propel downstream signaling. As with a typical glucagon GPCR pathway, the G-alpha subunit becomes activated upon guanine exchange factor [https://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factor (GEF)] echanging GDP for GTP. This G-alpha subunit transverses laterally in the membrane towards adenylyl cyclase, activating it and causing an increase in the second messenger cyclic adenosine monophosphate [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate (cAMP)]. This cAMP activates protein kinase A [https://en.wikipedia.org/wiki/Protein_kinase_A (PKA)], which can phosphorylate other proteins facilitating cellular response. | ||
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====Amidated C-Terminus==== | ====Amidated C-Terminus==== | ||
The <scene name='10/1038819/Amidated_c_term/9'>C-Terminus</scene> of amylin contains an amide group, rather than a carboxylic acid group. This chemical modification allows for more extensive hydrogen bonding to nearby residues, due to the added hydrogen bond donor on the NH2 group. In turn, this allows for favorable hydrogen bonds between S129 of the transmembrane domain and the main chain of Y37 on amylin. This interaction causes a "kink" in the random coil of amylin, displacing Y37 into a hydrophobic pocket, allowing for favorable hydrophobic interactions with W79 of the transmembrane domain. This amidation is thought to be a post-translational modification. <ref name="Vekic">PMID: 36005584</ref> | The <scene name='10/1038819/Amidated_c_term/9'>C-Terminus</scene> of amylin contains an amide group, rather than a carboxylic acid group. This chemical modification allows for more extensive hydrogen bonding to nearby residues, due to the added hydrogen bond donor on the NH2 group. In turn, this allows for favorable hydrogen bonds between S129 of the transmembrane domain and the main chain of Y37 on amylin. This interaction causes a "kink" in the random coil of amylin, displacing Y37 into a hydrophobic pocket, allowing for favorable hydrophobic interactions with W79 of the transmembrane domain. This amidation is thought to be a post-translational modification. <ref name="Vekic">PMID: 36005584</ref> | ||
==== Transmembrane Domain ==== | |||
Within the transmembrane domain (TMD) of the CTR, hydrophobic R groups span the phospholipid bilayer, anchoring the protein into the cell membrane upon amylin binding to the receptor. The interior of the transmembrane domain contains the hydrophilic residues necessary for ligand binding and transduction of the signal across the cell membrane. | |||
==== Bypass Motif ==== | ==== Bypass Motif ==== | ||
[[Image:SCT_rAmy_Overlay_v2.png|200 px|left|thumb|Figure 1: Overlay of sCT (orange) without the bypass motif and rAmy containing the bypass motif (green).]] | [[Image:SCT_rAmy_Overlay_v2.png|200 px|left|thumb|Figure 1: Overlay of sCT (orange) without the bypass motif and rAmy containing the bypass motif (green).]] | ||