The Role of Oligomerization in G Protein-Coupled Receptor Maturation
Bibliographic record
Abstract
A large body of evidence now shows that the basic functional unit of seven transmembrane-spanning G protein-coupled receptors (GPCRs) is a dimer, with the possibility of the existence of higher order oligomeric species. GPCR oligomerization has been demonstrated to be a physiological process that defines receptor pharmacology and function ( 1 , 2 ). There is substantial evidence indicating that these receptors are assembled as dimers and, possibly, oligomers prior to cell-surface expression ( Fig. 1 ). Although it has generally been accepted that constitutive GPCR oligomers exist at the plasma membrane, there is evidence demonstrating that the extent of oligomerization at the plasma membrane may be altered by ligand induction ( 3 – 5 ) ( Fig. 1 ). For many other classes of cell-surface receptors, oligomerization has been found to be a prerequisite for activation and signaling. For example, the epidermal growth factor receptor, a prototypical member of the tyrosine kinase (TK) family, requires a ligand-induced dimeric configuration for the auto-phosphorylation of tyrosine residues on the cytoplasmic domain and subsequent recruitment of various signaling proteins ( 6 ). With the exception of the insulin receptor, agonist-induced dimerization appears to be the rule of thumb for TKs. Conversely, a large proportion of receptors belonging to the cytokine receptor superfamily have been reported as intracellularly derived dimers at the plasma membrane ( 7 – 10 ). Ligand binding triggers a conformational change in these receptors, facilitating Janus kinase-mediated phosphorylation of various cytosolic substrates ( 11 ). Although there is a wealth of knowledge regarding the formation and functional significance of oligomerization in these other receptor families, progress is still being made to determine the cellular implications of the relatively novel concept of GPCR oligomerization. Maturation process of a GPCR oligomer. GPCR monomers are synthesized in the endoplasmic reticulum (ER) and inserted in the membrane sequentially as transmembrane domain pairs ( 1 ). Folding of the polypeptide is mediated by specific ER-resident molecular chaperones, which may also function to mediate dimeric assembly ( 2 , 3 ). Higher order oligomeric assembly may occur with other dimers in the ER (4A) and these complexes will then be trafficked to the cell surface as constitutively formed GPCR oligomers (5A). Alternatively, ER-formed dimers may traffic to the plasma membrane (4B, 5B) and form higher order oligomeric units upon agonist induction. These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".