β-barrel membrane proteins fold via hybrid-barrel intermediate states

Gram-negative bacteria and eukaryotic organelles of bacterial origin contain outer membrane proteins that possess a transmembrane “β-barrel” domain. The conserved β-barrel assembly machine (BAM) and the sorting and assembly machine (SAM) are required for the folding and membrane insertion of β-barrels in Gram-negative bacteria and mitochondria, respectively. Although the mechanisms by which β-barrels are folded are incompletely understood, advances in cryo-electron microscopy (cryo-EM) have recently yielded unprecedented insights into their folding process. Here we highlight recent studies that show that both bacterial and mitochondrial β-barrels fold via the formation of remarkable “hybrid-barrel” intermediate states during their interaction with the folding machinery. We discuss how these results align with a general model of β-barrel folding.