We propose a concept for the folding and self-assembly of the pore-forming TatA complex from the Twin-arginine translocase and of other membrane proteins based on electrostatic "charge zippers." Each subunit of TatA consists of a transmembrane segment, an amphiphilic helix (APH), and a C-terminal densely charged region (DCR). The sequence of charges in the DCR is complementary 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 transmembrane 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 monitoring the monomer-oligomer equilibrium of specific charge mutants. Similar "charge zippers" are proposed for other membrane-associated proteins, e.g., the biofilm-inducing peptide TisB, the human antimicrobial peptide dermcidin, and the pestiviral E(RNS) protein.
Many vital cellular processes, such as protein translocation, proton transport or\ud
molecular recognition, are mediated by self assembling membrane proteins.\ud
We have investigated the Twin-arginine translocase (TatA) complex, which\ud
forms transient pores through which proteins are translocated through the\ud
membrane. We postulated that complex formation is electrostatically driven\ud
by formation of salt bridges between amphiphilic transmembrane segments\ud
of the individual monomers and developed a structure-based model for this\ud
process[1].\ud
We studied the formation of oligomers of different sizes by structure-based[2]\ud
MD simulations in combination with NMR constraints and a hydrophobic-slab\ud
implicit membrane model. Starting from isolated monomers, distributed far\ud
apart from each other, we observed the formation of stable TatA oligomers\ud
on the basis of the postulated interactions. The dimensions of the resulting\ud
TatA complex agreed well with experimental electron microscopy measure-\ud
ments[3] and the postulated interactions were confirmed by subsequent muta-\ud
tion studie
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