Sandbox Ben Whiteside: Difference between revisions

When consuming food, the human body is tasked with secreting hormones and chemical messengers that will help regulate homeostasis. After a meal, the body has to maintain homeostasis by reducing blood glucose and signaling that enough nutrients have been consumed. During feeding, cells in the body will secrete the ligand, amylin. [https://en.wikipedia.org/wiki/Amylin Amylin] is a 37 amino acid glucoregulatory hormone that is produced within [https://en.wikipedia.org/wiki/Beta_cell beta cells] of the pancreas. When there is an influx of nutrients in the gastrointestinal tract, the ligand will bind to the heterodimeric receptor, activating the receptor and triggering the corresponding signaling cascade. The overall effect of this cascade is increased satiety, delayed gastric emptying, and inhibition of [https://en.wikipedia.org/wiki/Glucagon glucagon] secretion <ref name="Bower">PMID:27061187</ref>. The amylin receptors are widely distributed throughout the central nervous system <ref name="Hay">PMID:26071095</ref>. The amylin [https://en.wikipedia.org/wiki/G_protein-coupled_receptor g-protein coupled receptor] <scene name='10/1038828/Entire_protein_scene/4'>(AMYR) </scene>is a heterodimeric protein containing a [https://en.wikipedia.org/wiki/Calcitonin calcitonin] receptor domain, as well as one of three [https://en.wikipedia.org/wiki/Receptor_activity-modifying_protein receptor activity modifying proteins] (RAMP 1,2, or 3)<ref name="Cao">PMID:35324283</ref>.  

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.​

=== 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.   

====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.

=== Two-Domain Model of Amylin Binding ===

It is hypothesized that amylin binds to the receptor via a two-domain model. The model suggests a series of steps for how amylin binds. First, the c-terminus of amylin binds to the n terminus of the extracellular domain of the receptor. This binding factors the alignment of amylin's n-terminus to the primary GPCR binding site. Once both the c-terminus and n-terminus of amylin are bound, the receptor becomes activated [[Image:Domain_drawingnew.jpg|300px|left|thumb|Figure 1: The Two Domain Model]]