Folding and Self-Assembly of the TatA Translocation Pore Based on a Charge Zipper Mechanism.

We propose a concept for the folding and self- assembly of the pore-forming TatA complex from the Twin-arginine translocase and of other mem- brane proteins based on electrostatic ''charge zippers.'' Each subunit of TatA consists of a trans- membrane segment, an amphiphilic helix (APH), and a C-terminal densely charged region (DCR). The sequence of charges in the DCR is complemen- tary to the charge pattern on the APH, suggesting that the protein can be ''zipped up'' by a ladder of seven salt bridges. The length of the resulting hairpin matches the lipid bilayer thickness, hence a trans- membrane pore could self-assemble via intra- and intermolecular salt bridges. The steric feasibility was rationalized by molecular dynamics simulations, and experimental evidence was obtained by moni- toring the monomer-oligomer equilibrium of specific charge mutants. Similar ''charge zippers'' are pro- posed for other membrane-associated proteins, e.g., the biofilm-inducing peptide TisB, the human antimicrobial peptide dermcidin, and the pestiviral ERNS protein.