The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

Abstract

Running title (40 characters):Headgroup selectivity of an amphipathic helix Keywords:Opi1; phosphatidic acid; PA sensor; amphipathic helix; membrane curvature . CC-BY-ND 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/250019 doi: bioRxiv preprint first posted online Jan. 18, 2018; Page 2 of 43 Abstract (175 words limit)A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS).The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.

Unique Amphipathicα-helix Drives Membrane Insertion and Enzymatic Activity of ATG3

“…Fine-tuning the relationship between structure at the atomistic resolution, membrane lipid composition, and dynamics could be a general feature for AHs involved in cellular processes (46,47). We propose to move beyond simplified models, which are based exclusively on one biophysical property, to a more nuanced understanding of the role played by AHs.…”

Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P ₂ Synthesis

“…Accordingly, PM targeting of the PIP5K AH is specified by basic residues within the AH that bind PI4P and PS (and PA) in the cytoplasmic leaflet of the PM and is further stabilized by interactions with sterols ( Figure 7). Thus, the PIP5K AH is endowed with distinctive chemical and physical properties, compared to previously described AH membrane sensors (Bigay and Antonny, 2012;Covino et al, 2018;Hofbauer et al, 2018), allowing it to detect a unique PM environment containing PI4P, PS, and sterol. Although PIP5K AH targeting to the PM depended on both PS and PI4P, our analyses indicate increased binding affinity for PI4P over PS.…”