Nouvelles perspectives pour comprendre la reconnaissance des défauts d'empaquetage lipidique par le senseur de courbure membranaire ALPS (Amphipathic Lipid Packing Sensor)

The research about membrane-shape related processes is a new fascinating field. Recently an increasing number of lipid-binding domains that sculpt or sense the shape of the membrane have been identified. Most of the studies about membrane-shape have been focus on the generation of the curvature and less attention has been put on the mechanism of curvature sensing. Thus, this fascinating subject remains less understood. Recently, a general motif for sensing membrane curvature was proposed based on the properties of ALPS (ArfGAP1 Amphiphatic Lipid packing Sensor). This motif folds in an amphipathic !-helix once bound to the interface of membranes, has a populated serine/threonine polar face and hydrophobic aromatic residues rich hydrophobic face. Its membrane interaction depends on the recognition of defects in lipid packing and not in electrostatic charges. We performed molecular dynamics simulations of the amphipathic helical peptide ALPS, and a triple-mutant that experimentally compromises the sensitivity of ALPS to the membrane curvature. Both peptides were embedded at the water/lipid interface of explicit simple and mixed phosphatidylcholine membranes and simulations over 300 ns were run. In this thesis, we propose a novel atomistic view of ALPS curvature sensor lipid-packing recognition, where the dynamics and plasticity of both, ALPS and the membrane, act and adapt in a perfect synchony. We propose that ALPS is able to adapt to these inhomogeneities of the membrane thanks to the conformational deformability and structural flexibility that allow it to explore the lipid packing defects at the level of the polar heads and the acyl chains. This deformability is favor by a bulky-small&polar-bulky pattern that dispose the bulky hydrophobic residues and the small polar residues in a way that favors peptide-lipid interactions. Moreover we suggest that ALPS can induce adaptative dynamic response of the membrane that leads to a bilayer-coupling effect and a reciprocal orchestrated adaptation process. We show how the absence of lipid-packing defects avoid ALPS deformability and structural flexibility, affecting in consequence important intra-peptide and lipid-peptide interactions. Our results show that the deformability and structural flexibility of ALPS and the presence of lipid-packing defaults in the membrane are correlated. We also propose that the deformability is environment-dependent whereas the structural flexibility depends on the particularities of the sequence. Hence, ALPS plasticity must be of relevance for its curvature sensitivity. We advance that this could imply a concertated mechanism to recognize curved membranes. The partitioning of ALPS at the interfacial phosphate/glycerol level, suggest an adaptive interplay between the peptidesequence geometrical and space restrictions, the lipids conformations and the physical forces that shape the membrane.Des motifs structuraux largement impliqués dans les processus de modulation de la courbure membranaire sont les hélices amphipathiques. Parmi eux, un senseur de la courbure exhibant des propriétés particulières a été identifiée récemment : ALPS (ArfGAP1 Amphipathic lipid packing sensor). Il a été montré que son interaction avec la membrane était indépendante des charges Žlectrostatiques En effet, le modèle actuel suggère que les résidus hydrophobes soient les responsables de l'ancrage d'ALPS ˆ la membrane en reconaissant les défauts d'empaquetage lipidique. Par simulations par dynamique moléculaire des différentes membranes lipidiques avec le motif ALPS, nous montrons que ce senseur exhibe une considérable liberté conformationnelle et structurelle qui l'habilitent ˆ explorer les défauts d'empaquetage aux niveaux des têtes polaires ainsi qu'au niveau des chaînes aliphatiques. Nous proposons des nouvelles perspectives au niveau atomique de la reconnaissance des défauts d'empaquetage lipidique par ALPS o la déformabilité et flexibilité structurale ainsi que les propriétés dynamiques et physiques de la membrane jouent un r™le prépondérant