Predicting giant transmembrane β-barrel architecture.

Abstract

The β-barrel is a ubiquitous fold that is deployed to accomplish a wide variety of biological functions including membrane-embedded pores. Key influences of β-barrel lumen diameter include the number of β-strands (n) and the degree of shear (S), the latter value measuring the extent to which the β-sheet is tilted within the β-barrel. Notably, it has previously been reported that the shear value for small antiparallel β-barrels (n≤24) typically ranges between n and 2n. Conversely, it has been suggested that the β-strands in giant antiparallel β-barrels, such as those formed by pore forming cholesterol-dependent cytolysins (CDC), are parallel relative to the axis of the β-barrel, i.e. S=0. The S=0 arrangement, however, has never been observed in crystal structures of small β-barrels. Therefore, the structural basis for how CDCs form a β-barrel and span a membrane remains to be understood. Through comparison of molecular models with experimental data, we are able to identify how giant CDC β-barrels utilize a 'near parallel' arrangement of β-strands where S=n/2. Furthermore, we show how side-chain packing within the β-barrel lumen is an important limiting factor with respect to the possible shear values for small β-barrels (n≤24 β-strands). In contrast, our models reveal no such limitation restricts the shear value of giant β-barrels (n>24 β-strands). Giant β-barrels can thus access a different architecture compared with smaller β-barrels.