Membrane binding modes of the most common lipid-binding domains. A: C1 domain hydrophobic interactions facilitate the docking to the bilayer for efficient DAG or phorbol ester coordination. B: PH domains can bind a variety of PIs as described in the text. Some PH domains primarily associate with the membrane through electrostatic interactions with the PI, while a number of PH domains anchor to the membrane upon PI docking through penetration of hydrophobic residues adjacent to the PI binding site. PIs induce the membrane penetration of PX domains through a reduction in the desolvation penalty surrounding exposed hydrophobic residues adjacent to the PI binding site. The ENTH domain coordinates PIP₂, which induces formation of a N-terminal α-helix from an unstructured region. The amphipathic α-helix then inserts into the membrane to induce changes in membrane curvature. C: FYVE domains selectively bind PtdIns(3)P at a site adjacent to the hydrophobic membrane protrusion loop. Following nonspecific electrostatic association, PtdIns(3)P docking to FYVE domains induces the membrane penetration through a reduction of the desolvation penalty. D: Two modes of binding are depicted for C2 domains. Ca²⁺ ions are shown in yellow. Ca²⁺-binding C2 domains can associate with anionic or zwitterionic membranes depending upon the residues present in their Ca²⁺-binding loops. Some C2 domains contain a patch of cationic residues in their β-groove that is able to bind lipids such as PIs and may function in coincidence detection. E: Many BAR domains resemble the shape of a crescent moon and are rich in cationic residues on their concave surface. Thus, many BAR domains selectively associate with membranes of high curvature due to the shape of their concave surface and the greater ability for facilitating electrostatic interactions with the highly curved membranes.

Illustration of future directions of lipid-binding domain research. A: Future directions will be geared toward integration of new technologies to perform whole-animal studies with translational capabilities. Combining single molecule imaging of protein dynamics with quantitative lipid sensing could lead to an unprecedented view of the molecular architecture of signaling complexes. Computational biology will serve to predict signaling cascades, drug targets, and the effects of drug compounds on the disease state of the cell. B: Depiction of how new technologies will be applied to live cell studies.