InterPro: IPR006311 Twin-arginine translocation pathway, signal sequence

The twin-arginine translocation (Tat) pathway serves the role of transporting folded proteins across energy-transducing membranes [1]. Homologues of the genes that encode the transport apparatus occur in archaea, bacteria, chloroplasts, and plant mitochondria [2]. In bacteria, the Tat pathway catalyses the export of proteins from the cytoplasm across the inner/cytoplasmic membrane. In chloroplasts, the Tat components are found in the thylakoid membrane and direct the import of proteins from the stroma. The Tat pathway acts separately from the general secretory (Sec) pathway, which transports proteins in an unfolded state [3].

It is generally accepted that the primary role of the Tat system is to translocate fully folded proteins across membranes. An example of proteins that need to be exported in their 3D conformation are redox proteins that have acquired complex multi-atom cofactors in the bacterial cytoplasm (or the chloroplast stroma or mitochondrial matrix). They include hydrogenases, formate dehydrogenases, nitrate reductases, trimethylamine N-oxide (TMAO) reductases and dimethyl sulphoxide (DMSO) reductases [4, 5]. The Tat system can also export whole heteroligomeric complexes in which some proteins have no Tat signal. This is the case of the DMSO reductase or formate dehydrogenase complexes. But there are also other cases where the physiological rationale for targeting a protein to the Tat signal is less obvious. Indeed, there are examples of homologous proteins that are in some cases targeted to the Tat pathway and in other cases to the Sec apparatus. Some examples are: copper nitrite reductases, flavin domains of flavocytochrome c and N-acetylmuramoyl-L-alanine amidases [6].

In halophilic archaea such as Halobacterium almost all secreted proteins appear to be Tat targeted. It has been proposed to be a response to the difficulties these organisms would otherwise face in successfully folding proteins extracellularly at high ionic strength [7].

The Tat signal peptide consists of three motifs: the positively charged N-terminal motif, the hydrophobic region and the C-terminal region that generally ends with a consensus short motif (A-x-A) specifying cleavage by signal peptidase. Sequence analysis revealed that signal peptides capable of targeting the Tat protein contain the consensus sequence [ST]-R-R-x-F-L-K. The nearly invariant twin-arginine gave rise to the pathway's name. In addition the h-region of Tat signal peptides is typically less hydrophobic than that of Sec-specific signal peptides [4, 5].

Proteins assembled with various cofactors or by means of cytosolic molecular chaperones are poor candidates for translocation across the bacterial inner membrane by the standard general secretory (Sec) pathway. This entry describes a family of predicted long, non-Sec signal sequences and signal-anchor sequences (uncleaved signal sequences). A large fraction of the members of this family may have bound redox-active cofactors [8, 9].