Dystrophin is essential for skeletal muscle function and confers resistance to the sarcolemma by interacting with cytoskeletal and membrane partners. We previously showed that a large part of the rod domain of dystrophin interacts with membrane lipids. Amongst the central region, spectrin like repeats 11 to 15 (DYS R1115) constitutes an actin binding domain ABD2 as well as a lipid binding domain (Legardinier et al. J.Mol.Biol. 389:54658 2009). In this work, we aimed to characterize the specific proteinlipid interactions of DYS R1115. First, we show that DYS R1115 displays a strong amphiphilic character at the liquid/air interface while maintaining its αhelical secondary structure. We demonstrated that DYS R1115 strongly interacts with anionic small unilamellar vesicles, while only a weak binding is observed with zwitterionic small unilamellar vesicles and large anionic and zwitterionic vesicles, suggesting a binding dependent upon lipid charges and curvature or packing. Strikingly, it appears that the protein binds strongly to lipid monolayers with both anionic and zwiterrionic lipids; in addition, upon increase of surface pressure, regular protein networks are observed by AFM at the monolayer surfaces. This further indicates that the binding is dependent upon lipid packing. However, we observed that the accessibility to trypsin of DYSR1115 linked to monolayers depends on the phospholipid nature, suggesting a mode of proteinlipid binding also dependent on the lipid charges. This was confirmed by using trypsin proteolysis of the protein in the presence of vesicles with different radius. Labelfree quantification mass spectroscometry data showed that several regions of DYS R1115 are protected from trypsin action when the protein is in contact with anionic small unilamellar vesicles while another domain is found more subject to proteolysis in the presence of either anionic or zwitterionic vesicles. All together, our results indicate that DYS R1115 constitutes part of the dystrophin protein interacting with anionic as well as zwitterionic lipids, while the anchoring and interaction with membrane mostly depends on the lipid packing. Such behaviour, in addition to actin binding properties, provides a strong experimental support for a physiological role of dystrophin central domain on sarcolemma scaffolding upon contractionrelaxation cycles and dynamics of muscle cells.