Would you expect to activate RTKs by exposing the exterior...

Would you expect to activate RTKs by exposing the exterior of cells to antibodies that bind to the respective proteins? Would your answer be different for GPCRs? (Hint: review Panel $4-3$, on pp. $164-165,$ regarding the properties of antibody molecules.)

Key Concepts

Receptor Tyrosine Kinase (RTK) Activation

RTKs are activated by ligand-induced dimerization, which brings the intracellular kinase domains together to phosphorylate each other. Antibodies, because of their bivalent nature, can potentially cross-link RTKs by binding to two receptor molecules simultaneously, which might mimic the effect of natural ligands to a certain extent. However, whether an antibody acts as an agonist depends on its specific epitope and how it positions the receptors relative to one another.

G Protein-Coupled Receptors (GPCR) Activation

GPCRs function through conformational changes induced by ligand binding, typically involving a single transmembrane receptor that interacts with heterotrimeric G proteins. Unlike RTKs, GPCR activation is not strongly linked to dimerization; thus, antibody binding to the extracellular domain is less likely to induce the proper conformational changes required for activation. As a result, using antibodies to activate GPCRs generally does not replicate the effects of natural ligands.

Antibody Structure and Bivalency

Antibodies possess two antigen-binding sites, enabling them to bind to two copies of an antigen simultaneously. This property can lead to the cross-linking of cell surface receptors, which in some cases may mimic ligand-induced receptor aggregation or dimerization. However, the effectiveness of this mechanism greatly depends on the spatial requirements and activation mechanisms of the receptors involved.

Transcript

00:01 Hey everybody, so this question is giving us a hypothetical scenario where we're asked if we think that rtks can be activated by antibodies that are going to bind them and how this would be different with gpcrs.

00:22 So rtks.

00:23 So rtk stands for receptor tyrosine kinase, and these are going to be signaling kinases that are going to be present on the alt.

00:31 Outside of cells or transmembrane proteins, and they are activated by dimerization.

00:42 The way that rtks are activated here is we have one rtk here embedded in the membrane, we have another one over here.

00:50 Now in order for them to become activated, they actually have to come together and dimerize.

00:58 And this causes a, their kinase activity is going to phosphorylate them, so they're going to cross phosphorylate each other.

01:08 And this is going to activate the signaling cascade here.

01:12 And so this is in contrast with gpcrs, right? so gpcr stands for g protein coupled receptor.

01:21 We have g protein coupled receptors.

01:27 So gpcr.

01:28 And they have these seven transmembrane regions, right? so 1, 2, 3, 4, 5, 6, 7.

01:38 So gpcr are going to look kind of like this, embedded in the membrane.

01:43 And in order to activate a gpcr, we have to have a specific ligand to receptor interaction here.

01:52 So a specific ligand is going to come and bind to the gpcr.

01:56 And that's going to cause a conformational change within this membrane brown, membrane brown, receptor and that's going to then go ahead and have our intracellular signaling cascade take place...

Please give Ace some feedback