The Gβγ Dimer Drives the Interaction of Heterotrimeric Gi Proteins with Nonlamellar Membrane Structures

Abstract

G protein-coupled receptors (GPCRs) 1 constitute the main class of membrane receptors and form the widest gene family known in the mammalian genome. Therefore, signal transduction via G proteins represents one of the most important ways of cell signaling (for a review, see Ref. 1). Upon activation by agonists, GPCRs undergo conformational changes that induce the activation of heterotrimeric G proteins, promoting the exchange of the GDP bound to the G␣ subunit for GTP. This exchange provokes the dissociation of the G␣ subunit from the G␤␥ dimer and enables both molecular entities to modulate the activity of specific effectors or other signaling proteins (e.g. G protein receptor kinases).The association of both GPCRs and G proteins to the plasma membrane makes them susceptible to their lipid environment so that lipid-protein interactions are crucial to their function. In recent years, evidence has accumulated showing that the plasma membrane organization is more complex than a simple "chaotic sea" of bipolar lipid molecules in a liquid-crystalline state that only serves to support membrane proteins (2). In fact, differentiated membrane domains with specific protein and lipid compositions can exist in a cell such as the basal and apical membranes of epithelial/endothelial cells, the pre-and postsynaptic membranes of neuronal synapses, or lipid rafts and caveolae. Moreover, the extracellular and cytosolic leaflets of the plasma membrane differ in their lipid composition (3), further demonstrating the relevance of lipids in the organization and function of the membrane. Natural membranes are composed of different amphitropic molecules that differ in their propensity to form secondary lipid structures that influence the structural properties of the membrane (for a review, see Ref. 4). In this context, hexagonal (H II ) structures regulate the localization and activity of some key membrane signaling proteins (5, 6). Indeed, we have recently been able to show that changes in the lipid composition of erythrocyte cell membranes can influence the membrane association of G proteins and protein kinase C in vivo (7). Moreover, the neural membranes of cold-adapted fishes contain higher levels of phosphatidylethanolamine (PE) species in winter than in summer (8). These lipid changes probably lower the solidto-liquid and lamellar-to-hexagonal phase transition temperatures of membranes to maintain protein function and cell signaling in neurons and other cells. These data suggest that hexagonal phase propensity plays a major role in regulating physiological processes and might also participate in the control of other pivotal cellular events influenced by membrane proteins, such as cell growth or energy metabolism.Our main goal was to elucidate the role of the membrane lipid structure in the association to membranes of heterotrimeric G proteins and the molecular entities formed after their receptor-mediated activation. For this purpose we used synthetic membranes (liposomes) and purified G proteins as model systems because their li...

Oleic acid content is responsible for the reduction in blood pressure induced by olive oil

“…In this scenario, bulky isoprenyl moieties, such as those found through the posttranslational modification of the G␥ subunits of trimeric G proteins, can be inserted into membrane microdomains with a loose surface packing (i.e., high nonlamellar-phase propensity), whereas they are excluded from microdomains with tight packing such as lipid rafts. G protein heterotrimers prefer H II -prone regions, whereas G␣i monomers prefer lamellar-prone structures (e.g., lipid rafts) where myristic and palmitic acids (saturated fatty acids) can be readily inserted (25). These preferences may account for the reduction in G␣ proteins observed in membranes of animals that have a high OA intake.…”

“…The presence of the nonlamellar-prone lipid, OA, in the lipid bilayer induces a decrease in the surface packing of phospholipid headgroups (34,35). In turn, this favours the docking of certain peripheral signaling proteins involved in the control of BP (e.g., G proteins and PKC) (5,25). In this scenario, bulky isoprenyl moieties, such as those found through the posttranslational modification of the G␥ subunits of trimeric G proteins, can be inserted into membrane microdomains with a loose surface packing (i.e., high nonlamellar-phase propensity), whereas they are excluded from microdomains with tight packing such as lipid rafts.…”

“…Free or esterified, OA can modify the biophysical properties of membranes, specifically increasing the nonlamellar (H II ) phase propensity of the membrane (2, 3). In turn, this modification affects the docking of important membrane-associated signal transduction proteins involved in controlling BP, such as G proteins (1,24,25). In fact, altered levels and function of G proteins have been reported in both hypertensive humans (26,27) and experimental models of hypertension (28,29).…”

2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy

“…In line with these results, the addition of SM to culture medium enhances gemcitabine-mediated pancreatic cancer cell death (29) further indicating the relevance of this lipid in cancer cell survival. On the other hand, 2OHOA treatments induced specific changes in the levels of other membrane lipids (DAG, PE, and 2OHOA) that contributed to remodel membrane microdomains and regulated glioma cell signaling (30)(31)(32). These changes also facilitated the membrane binding and activation of PKCα (4, 10, and Fig.…”

Interactions of fatty acids with phosphatidylethanolamine membranes: X-ray diffraction and molecular dynamics studies

“…In fact, PE lipids have an intrinsic propensity to segregate forming nonlamellar H II structures in vitro ( 9 ), and some special features were attributed to H II -prone phospholipids, such as the functional control of membrane proteins and the structural organization inside cells (10)(11)(12). On the other hand, FAs incorporated in phospholipids or present in the membrane in their unesterifi ed form are able to modulate the structure of model PE membranes by interacting specifi cally with the latter ( 13,14 ).…”