Electrostatic and lipid anchor contributions to the interaction of transducin with membranes: mechanistic implications for activation and translocation.
The heterotrimeric G protein transducin is a key component of the vertebrate phototransduction cascade. Transducin is peripherally attached to membranes of the rod outer segment, where it interacts with other proteins at the membrane-cytosol interface. However, upon sustained activation by light, the dissociated G(t)alpha and Gbeta(1)gamma(1) subunits of transducin translocate from the outer segment to other parts of the rod cell. Here we used a computational approach to analyze the interaction strength of transducin and its subunits with acidic lipid bilayers, as well as the range of orientations that they are allowed to occupy on the membrane surface. Our results suggest that the combined constraints of electrostatics and lipid anchors substantially limit the rotational degrees of freedom of the membrane-bound transducin heterotrimer. This may contribute to a faster transducin activation rate by accelerating transducin-rhodopsin complex formation. Notably, the membrane interactions of the dissociated transducin subunits are very different from those of the heterotrimer. As shown previously, Gbeta(1)gamma(1) experiences significant attractive interactions with negatively charged membranes, whereas our new results suggest that G(t)alpha is electrostatically repelled by such membranes. We suggest that this repulsion could facilitate the membrane dissociation and intracellular translocation of G(t)alpha. Moreover, based on similarities in sequence and electrostatic properties, we propose that the properties described for transducin are common to its homologs within the G(i) subfamily. In a broader view, this work exemplifies how the activity-dependent association and dissociation of a G protein can change both the affinity for membranes and the range of allowed orientations, thereby modulating G protein function.
Kosloff
Mickey
M
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Alexov
Emil
E
Arshavsky
Vadim Y
VY
Honig
Barry
B
D000818:Animals; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D020836:Protein Structure, Quaternary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism*; D015293:Transducin
D008051:Lipid Bilayers; D021122:Protein Subunits; D012243:Rhodopsin; D015293:Transducin
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