Abstract
RGS proteins regulate the duration of G protein signaling by increasing the rate of GTP hydrolysis on G protein alpha subunits. The complex of RGS9 with type 5 G protein beta subunit (G beta 5) is abundant in photoreceptors, where it stimulates the GTPase activity of transducin. An important functional feature of RGS9-G beta 5 is its ability to activate transducin GTPase much more efficiently after transducin binds to its effector, cGMP phosphodiesterase. Here we show that different domains of RGS9-G beta 5 make opposite contributions toward this selectivity. G beta 5 bound to the G protein gamma subunit-like domain of RGS9 acts to reduce RGS9 affinity for transducin, whereas other structures restore this affinity specifically for the transducin-phosphodiesterase complex. We suggest that this mechanism may serve as a general principle conferring specificity of RGS protein action.
Highlights
From the ‡Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, §Boston Biomedical Research Institute, Watertown, Massachusetts 02472, ¶Tufts University School of Medicine, Boston, Massachusetts 02111, ʈMetabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892
The ability of RGS9-G5L to select between free transducin and transducin-PDE complex is achieved because its affinity for free transducin is lower than its affinity for transducin bound to PDE [13]
The promiscuity of RGS catalytic domains suggests that specificity in the interactions between RGS and G proteins is at least partially achieved through the action of additional domains and/or subunits with which many RGS proteins are equipped [2, 37]
Summary
From the ‡Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, §Boston Biomedical Research Institute, Watertown, Massachusetts 02472, ¶Tufts University School of Medicine, Boston, Massachusetts 02111, ʈMetabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892. Over 20 mammalian RGS proteins have been identified that regulate the GTPase activity of most known G protein ␣ subunits The abundance of both protein types, along with findings that catalytic domains of RGS proteins have a very poor ability to discriminate among different G protein ␣ subunits, makes the problem of specificity in the RGS-G protein interaction one of the most interesting questions in G protein signaling. This implies that the major role in conferring the stimulating effect of PDE␥ is played by other, noncatalytic domains of RGS9-G5L This idea has been recently supported by He et al [21], who reported that practically all domains within the RGS9-G5L complex contribute to its ability to discriminate between free activated transducin and transducin bound to PDE. All other parts of RGS9 as well as the N terminus of G5L restore this affinity for the transducin-
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