You have a gene that codes for a cell surface receptor that has a half-life of several days. As there is some potential for targeting this receptor for a particular disease based functionality, it's path of production and clearance is of special interest to a variety of large pharmaceutical firms. It is thought that these pathways could be modified were one to understand fully the particular membrane interactions that occur throughout the production clearance cycle of this receptor within the cells where it is produced. Please provide me with a list of the possible membranous entities and regions within these cells that are likely or essential to both this receptors' production and clearance. This information is sought as there is a region, highly conserved on this gene product that is seen as potentially modifiable in a manner that could alter the binding constants of the protein with each of the membranes involved in its production and clearance to affect this receptor's function in a useful manner.
Introduction
One of the cell surface receptor is known as the LDL receptor; also known as, the low density lipoprotein receptor. This receptor consists of approximately 840 amino acids. It is a chimeric protein as it consists of functionally distinct domains. One of its main functions is that it mediates the endocytosis of cholesterol rich lipoprotein. Lastly, this receptor is coded by LDLR gene (Krauss, 2008).
Gene Structure of the LDRLGene
The gene coding for the LDL receptor is split into 18 exons. Each exon has its own specific function which is listed below as follows:
1. Exon 1 helps in localizing the receptor to the endoplasmic reticulum from where it is transported to the cell surface.
2. Exon 2 through 7 codes the ligand binding region. It is a highly conserved region as on this gene, the product is easily modified by altering the binding constant of the protein.
3. Exon 7 through14 codes for EGFP domain.
4. Exon 15 codes for ollgo saccharide rich region.
5. Exon 16 and a part of Exon 17 codes for membrane spanning region.
6. Exon 18 and the remaining part of Exon 17 codes for the cytosolic domain.
The LDLR gene is located on the short (p) arm of chromosome 19 at position 13.2 (Murray, Granner, Mayes, & Rodwell, 2003).
Function of LDLR Receptor
The complexes of the receiver of LDL are present in mines clathrin - coated (or buds) on the surface of a cell, of which when tied to LDL-cholesterol via adaptin, it is pinched form vesicles clathrin - coated inside the cell. It allows the LDL-cholesterol to be tied and internalized in a known process called endocytosis and prevents the LDL from spreading around the membranous surface. It occurs in all cells nucleated (not erythrocytes), but especially in the liver which takes away approximately 70% of LDL within the circulation (Nelson, and Cox, 2008).
As soon as the coated vesicle is internalized it will spread the topcoat of clathrin and amalgamate with an acidic late endosome. A change in the pH level causes a change of conformational in the receiver which in turn liberates the linked up particle LDL. The receptors are then destroyed or they can be recycled via the endocytic cycle behind the surface of the cell where the pH level is neutral, thus causing the receptor to revert to its native conformation, ready to receive another LDL particle (Nelson, and Cox, 2008).
The synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol. If it is in excess for the needs of the cell then the transcription of the receptor gene will be inhibited. The LDL receptors are translated by ribosomes on the endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface. Mutations in the LDLR gene can cause an inherited form of high cholesterol called hypercholesterolemia (Nelson, and Cox, 2008).
A list of membranous entities within a cell that are essential for receptor production and clearance are listed below as follows:
1. Cholesterol - Level of intracellular cholesterol - Low levels of cholesterol within a cell causes receptor production and high level causes receptor clearance.
2. Endoplasmic reticulum - Translation of receptors by ribosomes on the endoplasmic reticulum causes receptor production.
3. Golgi complex - Modification of receptor by Golgi apparatus increases receptor production (Murray, Granner, Mayes, & Rodwell, 2003).
.Discussion Questions fropm Primary Assignment Saad Almasuod Jasmonate/Arachidonate response:
1. How is the LDL receptor transported to the cell surface? Process, how much detail is known?
2. Is the binding site easily modified or affected in any way during its synthesis and trafficking of the receptor to the cell surface? If so where and how?
3. What is the function of this conserved domain and what is the function of this receptor that you chose as an example in terms of its role in LDLR function?
4. In response 5 of your answer, what changes in the membrane spanning region, defined by Exons 16 and 17 are allowed? Many?, some? None?
5. What role/function is associated with the “cytosolic domain defined by Exons 18 and part of Exon 17?
6. Page 2 of your response, line 11; “The receptors are then destroyed or they can be recycled…..,How is this decided if it can do both?
7. Page 2, line 15; the synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol. Is this a general rule for plasma membrane bound receptors, i.e., are they regulated by their respective ligands?
8. Page 2, line 17; LDL receptors are translated by ribosomes on the endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface…How complex is this process? How many separate membrane, intracellular associated events occur throughout this process? How many are points of control?
You have provided a specific PM bound receptor as an example, but have focused on the conserved ligand binding site and membrane spanning region in the example you propose as fulfilling the requested response from the question asked. How would the knowledge you gained from the readings on Jasomonte signaling provide any openings for generating an answer to this question?