Reading the Lipid Code: Cooperative Domain Functions in Perilipin Targeting to Lipid Droplets

This is the authors' abstract. We don't add key points for this paper.

Perilipins (PLINs) are the most abundant proteins coating the phospholipid monolayer of lipid droplets (LDs), regulating their biogenesis, stability, growth, and lipolysis. Most mammalian isoforms (PLIN1-3, PLIN5) share a modular architecture characterized by an N-terminal PAT domain (perilipin-adipophilin-TIP47), a central 11-mer repeat region forming amphipathic helices (hydrophobic and hydrophilic faces on opposite sides of the helix), and a C-terminal 4-helix bundle; PLIN4 is a notable exception that relies mainly on expanded amphipathic helices. In this review, we synthesize recent structural, biophysical, and cell-biological advances and present a working framework in which these domains function cooperatively to read a local lipid code composed of diacylglycerol (DAG) enrichment, phospholipid composition, packing defects, and surface tension. The PAT domain preferentially engages DAG-rich endoplasmic reticulum (ER) subdomains to initiate recruitment and support LD budding. The 11-mer amphipathic helices, often weakly hydrophobic and highly repetitive, especially in PLIN4, recognize lipid packing defects and enable dynamic, tension-responsive binding, with polar residues supporting multimeric assembly and exceptional stability on LD surfaces. The C-terminal 4-helix bundle contains a conserved hydrophobic cleft that can accommodate phosphatidylethanolamine (PE); isolated domains prefer PE-rich interfaces, and PE limitation reduces cellular recruitment. Isoform-specific variations, including PLIN1's integral membrane segment for ER insertion and high-affinity binding, contribute to hierarchical sorting and LD heterogeneity. Together, these cooperative domain functions integrate lipid cues to orchestrate LD assembly and remodeling, with implications for metabolic diseases such as metabolic dysfunction-associated steatotic liver disease, obesity, and lipodystrophies.