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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.

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1 Answer 1

Polar amino acids in this case stabilize the helical structure within the apolar milieu of the membrane by making intra- and inter-helical connections. Thus the side chains of polar amino acids turn to one another while apolars face the apolar membrane. This would be definitely supported if you could find alternating apolar - polar segments in the sequence of helices.

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Thanks for the answer. You mean to say that the helices are closely packed that the polar residues are found where they contact each other and the apolar residues are probably more denser on the helices at the two extreme ends where they make contacts with the apolar milieu of the lipid bilayer that is the membrane. –  Curious Apr 28 at 6:57
    
Is this the only way around in this question ? Are there any other possibilities ? Could it be that one of the helices with the polar residues protrude into the cytosol to make contacts with the G-protein ? –  Curious Apr 29 at 14:15

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