The Hydrophobic Amino Acid Residues in the Membrane-Proximal C Tail of the G Protein-Coupled Vasopressin V2 Receptor are Necessary for Transport-Competent Receptor Folding
| Title: | The Hydrophobic Amino Acid Residues in the Membrane-Proximal C Tail of the G Protein-Coupled Vasopressin V2 Receptor are Necessary for Transport-Competent Receptor Folding |
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| Authors: | Thielen, Anja; Oueslati, Morad; Hermosilla, Ricardo; Krause, Gerd; Oksche, Alexander; Rosenthal, Walter; Schulein, Ralf |
| Publisher: | FEBS Letters |
| Date Published: | September 26, 2005 |
| Reference Number: | 696 |
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
The vasopressin V2 receptor (V2R) is a chain of 371 amino acid residues. Scientists postulate that part of it exists inside the cell, part within the cell membrane that forms the perimeter of the cell, and part exists outside the cell. The beginning of the V2R is outside the cell; it extends through the cell membrane into the cell interior, then back up through the membrane to the cell exterior. It does this several times. All told, there are four receptor segments that exist outside the cell. These are called N tail, and extracellular loops 2, 3 and 4. There are four segments inside the cell called intracellular loops 1, 2 and 3 and C tail. The V2R clusters inside the cell membrane in 7 distinct clusters called transmembrane helices.
Researchers study the structure and function of V2R for different reasons, one of which is the role it plays in the kidney’s ability to reabsorb water and concentrate urine. As V2R is synthesized and matures, it moves from the cell interior, through the endoplasmic reticulum and the golgi apparatus. These are quality control systems within the cell that assure that the synthesizing V2R protein is properly shaped and folded. If it is not, the V2R is held in these quality control systems and then dissolved. If the V2R is normal, it is released and traffics (i.e., moves) to its work station, the cell membrane. If it is misshapen, the V2R is held and not allowed to travel to the cell membrane. This can result in nephrogenic diabetes insipidus (NDI), which is characterized by the kidney’s failure to concentrate urine by reabsorbing water.
Thielen, et al., understood that V2R’s C tail plays a crucial role in the protein's ability to move to the cell membrane, and that two Leucine amino acids that were the 339th and 340th amino acids in the V2R chain were essential in order for V2R to move from the ER to the Golgi. The research team investigated whether other amino acid in C tail and nearby were also important to the V2R’s ability to transport out of the ER.
By manipulating the V2R’s amino acid residue chain, substituting different amino acids for select amino acids in the C tail that normally are present in those positions, Thielen, et al., were able to demonstrate that the amino acid phenylalanine (F) at position 328, valine (V) at position 332 and leucine (L) at position 336 (F328, V332 and L336, respectively) were also important to V2R’s movement to the cell membrane. The team also determined that the serine (S) amino acids at positions 330, 331, 333, 334 and 338 are not relevant to V2R’s movement out of the ER.
L339 and 340, F328, V332 and L336 are hydrophobic. That is, they do not readily dissolve in water. The serines mentioned are hydrophilic – they do not readily dissolve in water. The research team’s data strongly suggests that it was the hydrophobic residues that played a role in V2R movement, and they do so not by initiating a signal to begin a sorting process, but by helping the V2R to achieve its proper protein configuration so that it will be able to pass the quality control requirements of the ER.