Amino acid profile of GPCRs?

Question

> You are studying cellular signalling through a newly identified GPCR. Specifically you’re working on a pair of newly identified GPCRs, GPCR-A and GPCR-B. Each binds the same small ligand, but activates different heterotrimeric G-proteins that act on adenylyl cyclase. Your grad student mentor explains that both the receptors and the Gα and Gβγ subunits of the heterotrimeric G-proteins are membrane associated. You examine the sequences of the seven predicted transmembrane α-helices of GPCR-B. You’re surprised to find that there are hydrophilic amino acid residues in these helices. How can you explain this observation? This was an MIT quiz question.I have my guesses. But I wanted to know the correct answer.Well, since GPCRs are transmembrane proteins, normally the transmembrane helices have higher hydrophobic amino acids or only hydrophobic, non-polar aa . Here it says they saw some polar residues. Well my guess is that, since there are two GPCRs a and b that bind to the same ligand, it could be that one activates a stimulatory G protein and the other an inhibitory G protein Gi . So probably the polar amino acids which are in the transmembrane alpha helical segment of the stimulatory GPCR is slightly displaced and is in the intracellular region of the inhibitory GPCR (Gpcr that activates inhibitory G protein ). To be in the intracellular region, it has to be hydrophilic.This is all I can think of. Any help with this question is much appreciated. It is not a homework question for me. I don't go to MIT. I just wanted to reinforce my concepts.

Answer 1

Your answer makes sense to me. You're talking about a transmembrane helices that, well, span the membrane, that is they go from the outside of the cell, through the lipid bilayer, and some part protrudes to the inside of the cell. It makes perfect sense that there are hydrophilic residues, as these are most likely the residues that are on the outside and inside of the cell, that is they are in contact with the extracellular fluid and the cytosol. If this were a membrane channel there would probably be a larger portion of hydrophilic residues because they would have to line the inside of the channel.

Your answer is sound.

Best,

-Dr.B-