Andrew Helmerich Sandbox 1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 9: | Line 9: | ||
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. | 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. | ||
==== 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. | ||
====N-Terminus Disulfide==== | ====N-Terminus Disulfide==== | ||
The amylin peptide contains a <scene name='10/1038819/N_term_disulfide/ | The amylin peptide contains a <scene name='10/1038819/N_term_disulfide/4'>covalent disulfide linkage</scene> between residues C2 and C7. This disulfide provides stability and rigidity to the helical structure of the peptide, allowing for favorable binding to the extracellular domain (ECD). New interactions due to the disulfide include hydrogen bonds between E294 of the transmembrane domain with K1 of amylin, and both R362 and W361 of the transmembrane domain forming a hydrogen bond with N3 of amylin. | ||
====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> | ||