Structures of Ostα/β reveal a unique fold and bile acid transport mechanism.
Not reported in abstract.
Where it sits
this study against the rest of the matrixyl corpusSummary and findings
Not reported in abstract.
Abstract
Bile acid and steroid hormone homeostasis are critical for human health, with disruptions linked to metabolic and endocrine disorders<sup>1,2</sup>. The organic solute transporter Ostα/β, essential for bile acid efflux in enterohepatic circulation<sup>3</sup>, has long defied mechanistic elucidation. Here we present cryogenic electron microscopy structures of human Ostα/β in apo and substrate-bound states at 2.6-3.1 Å resolution, revealing a distinctive membrane protein architecture that defines a new transporter class. Ostα/β forms a symmetric tetramer of heterodimers, with each Ostα subunit showing a new seven-transmembrane fold, augmented by a single transmembrane helix of Ostβ. This architecture is stabilized by extensive lipid modifications, including a palmitoylated cysteine-rich motif that forms a lateral substrate-binding groove. The structures uncover a unique transport pathway featuring two substrate-binding sites connected by an amphipathic helix-gated conduit. This design, conserved in the evolutionarily related TMEM184 family, suggests an ancient mechanism for substrate translocation. Electrophysiological studies demonstrate voltage-sensitive, bidirectional transport driven by electrochemical gradients, elucidating the efflux role of Ostα/β in vivo. Lipid interactions, notably palmitoylation-dependent trafficking, emerge as critical for stability and function. These findings clarify the molecular mechanism of Ostα/β, provide a structural basis for disease-associated mutations<sup>4,5</sup> and establish a paradigm for lipid-modified membrane transport.
Background
Not reported in abstract.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Limitations
Not reported in abstract.