TM3 And The Dry Motif

In the rhodopsin family receptors, the highly conserved Arg350 in the DR*Y sequence at the cytosolic end of TM3 has been proposed to operate as an arginine switch (Figure 10.4B). The highly positive, large side chain was hypothesized to swing away from the receptor upon ligand binding, possibly being released from the conserved TM2 aspartate, Asp250, and to switch the G protein into an active conformation.40 The motif equivalent to the DRY sequence (ERY in rhodopsin) is EGLY in the secretin family receptors, which suggests that a negative charge and a tyrosine residue may also have a role in a common signal transduction mechanism. Arginine (and tyrosine) residues are often present at the cytosolic ends of TM helices, although this may be due to the general use of cationic residues as helix terminators in most transmembrane proteins (or possibly potential phosphorylation sites; see above).

The arginine "switch" concept has evolved into the concept of an arginine "cage" by the incorporation of a hydrophobic residue Val139354, which further restricts arginine movement.41 Interestingly, the universal, constitutively activating mutation position42 p2-AR Ala296634 is occupied by Thr251 in rhodopsin and lies adjacent to Arg135350, implying that its activating effect is by perturbation of the arginine switch. As mentioned above, Arg135350 is separated from Tyr296753 by only one hydrophobic residue, Leu722.39, suggesting that movement of the intracellular ends of TM helices 3 and 7 is coordinated during allosteric activation. This proposition has been condoned recently by the demonstration that constitutively activating mutations of the LH receptor involving Met389243 correlated with the size of the mutated residue.43 Tyr623753 in the LH receptor was identified as the residue perturbed by the larger substitutions, encouraging proximity modifications at the DRY motif which promoted constitutive activity.

Not only is TM3 the only continuous and unbroken helix of the seven, but also it has highly conserved residues at both ends, with ArglB.53-50 intracellularly and Cys110325 extracellularly (Figure 10.6B).

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