Selective binding of MLX to triacylglycerol-rich lipid droplets: Mechanisms of cytosolic localization and proteome regulation

The activation of transcription factor Max-Like Protein x (MLX) is modulated by competition between active dimerization and inactive association with cytosolic lipid droplets (LDs). This work explores how two MLX sequences inhibit activity, targeting either membranes broadly or LDs rich in triacylglycerol (TG) specifically. If applicable to other proteins in the MAX-network of transcription factors, this could offer a new direction for cancer therapeutics. The association mechanisms explain why targeting is specific, highlighting the physical properties of sterol ester-rich LDs that block association and thereby link lipid metabolic conditions to glucose metabolic regulation. Notably, MLX association is shown to be influenced by kinetics and to alter the surrounding LD monolayer. These findings demonstrate a dynamic interplay between protein association and membrane monolayer properties that enables cytosolic localization, targeting specificity, and potential kinetic and allosteric regulation of the LD proteome.