PT - JOURNAL ARTICLE AU - Yong Mi Choi AU - Dalila Ajjaji AU - Kaelin D. Fleming AU - Peter P. Borbat AU - Meredith L. Jenkins AU - Brandon E Moeller AU - Jack H. Freed AU - John E. Burke AU - Abdou Rachid Thiam AU - Michael V. Airola TI - Structure and dynamics of human perilipin 3 membrane association AID - 10.1101/2022.11.17.516819 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.11.17.516819 4099 - http://biorxiv.org/content/early/2022/11/17/2022.11.17.516819.short 4100 - http://biorxiv.org/content/early/2022/11/17/2022.11.17.516819.full AB - Lipid droplets (LDs) are dynamic organelles that contain an oil core mainly composed of triglycerides (TAG) that is surrounded by a phospholipid monolayer and LD-associated proteins called perilipins (PLINs). During LD biogenesis, perilipin 3 (PLIN3) is recruited to nascent LDs as they emerge from the endoplasmic reticulum. Here, we analyzed how lipid composition affects PLIN3 recruitment to membrane bilayers and LDs, and the structural changes that occur upon membrane binding. We found the TAG precursors phosphatidic acid and diacylglycerol (DAG) recruit PLIN3 to membrane bilayers and define an expanded PAT domain that preferentially binds DAG enriched membranes. Membrane binding induces a disorder/order transition of alpha helices within the PAT domain and 11-mer repeats, with intramolecular distance measurements consistent with the expanded PAT domain adopting a triangular tertiary structure. In cells, PLIN3 is recruited to DAG enriched ER membranes, and this requires both the PAT domain and 11-mer repeats. This provides molecular details of PLIN3 recruitment to nascent LDs and identifies a function of the PAT domain of PLIN3 in DAG binding.Competing Interest StatementJEB reports personal fees from Scorpion Therapeutics and Olema Oncology; and research grants from Novartis.