Abstract
The need to gain insights into the molecular details of peripheral membrane proteins’ specificity towards phosphatidic acid (PA) is undeniable. The variety of PA species classified in terms of acyl chain length and saturation translates into a complicated, enigmatic network of functional effects that exert a critical influence on cell physiology. As a consequence, numerous studies on the importance of phosphatidic acid in human diseases have been conducted in recent years. One of the key proteins in this context is mTOR, considered to be the most important cellular sensor of essential nutrients while regulating cell proliferation, and which also appears to require PA to build stable and active complexes. Here, we investigated the specific recognition of three physiologically important PA species by the mTOR FRB domain in the presence or absence of cholesterol in targeted membranes. Using a broad range of methods based on model lipid membrane systems, we elucidated how the length and saturation of PA acyl chains influence specific binding of the mTOR FRB domain to the membrane. We also discovered that cholesterol exerts a strong modulatory effect on PA-FRB recognition. Our data provide insight into the molecular details of some physiological effects reported previously and reveal novel mechanisms of fine-tuning the signaling cascades dependent on PA.
Highlights
Specificity towards phosphatidic acid (PA) is undeniable
To characterize the capacity of the FRB domain to bind PA-enriched membranes, we focused on phosphatidic acid molecules differing in the acyl chain structure
Previous studies revealed that mTOR activity in cells in vitro is dependent on PA and that the consequences of this interaction are determined by the structure of the lipid [39,40,41]
Summary
The variety of PA species classified in terms of acyl chain length and saturation translates into a complicated, enigmatic network of functional effects that exert a critical influence on cell physiology. We investigated the specific recognition of three physiologically important PA species by the mTOR FRB domain in the presence or absence of cholesterol in targeted membranes. Using a broad range of methods based on model lipid membrane systems, we elucidated how the length and saturation of PA acyl chains influence specific binding of the mTOR FRB domain to the membrane. Protein-lipid interactions still remain hard to explore and evaluate Studying such interactions in the context of living cells is challenging due to their complex architecture and very dynamic nature. For PA dozens of partner proteins involved in various processes in mammalian cells have been identified [10], no common PA-recognizing motif was described for these proteins [11,12,13]
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