The transporter–opsin–G protein‐coupled receptor (TOG) superfamily

Abstract

Visual Rhodopsins (VR) are recognized members of the large and diverse family of G protein-coupled receptors (GPCRs), but their evolutionary origin and relationships to other proteins, are not known. In an earlier publication (Shlykov et al., 2012), we characterized the 4-Toulene Sulfonate Uptake Permease (TSUP) family of transmembrane proteins, showing that these 7 or 8 TMS proteins arose by intragenic duplication of a 4 TMS-encoding gene, sometimes followed by loss of a terminal TMS. In this study, we show that the TSUP, GPCR and Microbial Rhodopsin (MR) families are related to each other and to six other currently recognized transport protein families. We designate this superfamily the Transporter-Opsin-G protein-coupled receptor (TOG) Superfamily. Despite their 8 TMS origins, members of most constituent families exhibit 7 TMS topologies that are well conserved, and these arose by loss of either the N-terminal (more frequent) or the C-terminal (less frequent) TMS, depending on the family. Phylogenetic analyses revealed familial relationships within the superfamily and protein relationships within each of the nine families. The statistical analyses leading to the conclusion of homology were confirmed using HMMs, Pfam, and 3D superimpositions. Proteins functioning by dissimilar mechanisms (channels, primary active transporters, secondary active transporters, group translocators and receptors) are interspersed on a phylogenetic tree of the TOG superfamily, suggesting that changes in the transport and energy-coupling mechanisms occurred multiple times during the evolution of this superfamily.

The twisted relation between Pnu and SWEET transporters

“…Such a connecting TM is also present in the full-length SWEET transporters giving rise to their 3+1+3 membrane topology. The similarity in membrane topology and domain organization between the Pnu and SWEET transporters had been noticed before, and is also predicted for other transporter families of the PQ loop superfamily [26].…”

Shared Molecular Mechanisms of Membrane Transporters

“…Each bundle of three TM segments is oriented with its N-and C-termini facing, respectively, extracellular or cytoplasmic solution (known as N out− -C in topology), as established by the positive-inside rule (37). The middle of TM1 in each bundle of three TM segments kinks outward at a highly conserved PQ-loop motif (38,39) to form two helical parts, TM1a and TM1b. TM1a packs against TM2 in the symmetrically related bundle to seal the two bundles together.…”

Structure and function of SemiSWEET and SWEET sugar transporters

“…Although heptahelical vitamin transporter PnuC and G protein-coupled receptors (GPCRs) were proposed to be related to SWEETs based on remote sequence pattern similarity and positions of the TM helices [24][25][26], their topologies differ from that of the SemiSWEET dimer. TMs of GPCR and PnuC core are connected sequentially, with each TM interacting with the next one in the sequence, which is in contrast to the 1-3-2 connectivity in THB of SemiSWEET.…”