Two parameters of biological membranes, curvature and lipid composition, direct the recruitment of many peripheral proteins to cellular organelles. Although these traits are often studied independently, it is their combination that generates the unique interfacial properties of cellular membranes. Here, we use a combination of in vivo, in vitro and in silico approaches to provide a comprehensive map of how these parameters modulate membrane adhesive properties. The correlation between the membrane partitioning of model amphipathic helices and the distribution of lipid-packing defects in membranes of different shape and composition explains how macroscopic membrane properties modulate protein recruitment by changing the molecular topography of the membrane interfacial region. Furthermore, our results suggest that the range of conditions that can be obtained in a cellular context is remarkably large because lipid composition and curvature have, under most circumstances, cumulative effects.

Phospholipids (PLs) with polyunsaturated acyl chains are extremely abundant in a few specialized cellular organelles such as synaptic vesicles and photoreceptor discs, but their effect on membrane properties is poorly understood. Here, we found that polyunsaturated PLs increased the ability of dynamin and endophilin to deform and vesiculate synthetic membranes. When cells incorporated polyunsaturated fatty acids into PLs, the plasma membrane became more amenable to deformation by a pulling force and the rate of endocytosis was accelerated, in particular, under conditions in which cholesterol was limiting. Molecular dynamics simulations and biochemical measurements indicated that polyunsaturated PLs adapted their conformation to membrane curvature. Thus, by reducing the energetic cost of membrane bending and fission, polyunsaturated PLs may help to support rapid endocytosis.

We have identified a novel ␤ amyloid precursor protein (␤APP) mutation (V715M-␤APP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked ␤APP mutations reported to date, overexpression of V715M-␤APP in human HEK293 cells and murine neurons reduces total A␤ production and increases the recovery of the physiologically secreted product, APP␣. V715M-␤APP significantly reduces A␤40 secretion without affecting A␤42 production in HEK293 cells. However, a marked increase in N-terminally truncated A␤ ending at position 42 (x-42A␤) is observed, whereas its counterpart x-40A␤ is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of A␤ but may be caused by increased production of truncated forms of A␤ ending at the 42 position.