Expansion of the Transporter-Opsin-G protein-coupled receptor superfamily with five new protein families

Abstract

Here we provide bioinformatic evidence that the Organo-Arsenical Exporter (ArsP), Endoplasmic Reticulum Retention Receptor (KDELR), Mitochondrial Pyruvate Carrier (MPC), L-Alanine Exporter (AlaE), and the Lipid-linked Sugar Translocase (LST) protein families are members of the Transporter-Opsin-G Protein-coupled Receptor (TOG) Superfamily. These families share domains homologous to well-established TOG superfamily members, and their topologies of transmembranal segments (TMSs) are compatible with the basic 4-TMS repeat unit characteristic of this Superfamily. These repeat units tend to occur twice in proteins as a result of intragenic duplication events, often with subsequent gain/loss of TMSs in many superfamily members. Transporters within the ArsP family allow microbial pathogens to expel toxic arsenic compounds from the cell. Members of the KDELR family are involved in the selective retrieval of proteins that reside in the endoplasmic reticulum. Proteins of the MPC family are involved in the transport of pyruvate into mitochondria, providing the organelle with a major oxidative fuel. Members of family AlaE excrete L-alanine from the cell. Members of the LST family are involved in the translocation of lipid-linked glucose across the membrane. These five families substantially expand the range of substrates of transport carriers in the superfamily, although KDEL receptors have no known transport function. Clustering of protein sequences reveals the relationships among families, and the resulting tree correlates well with the degrees of sequence similarity documented between families. The analyses and programs developed to detect distant relatedness, provide insights into the structural, functional, and evolutionary relationships that exist between families of the TOG superfamily, and should be of value to many other investigators.

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

“…MPC1 and MPC2 are small integral membrane proteins of, respectively, 12 kDa and 14 kDa. Structure predictions using different algorithms suggest that MPCs belong to the semi-SWEET (Sugar Will Eventually be Exported Transporter) domain family (SLC50 family) [ 13 ] or to the SWEET family [ 14 ], also known as the PQ-loop family of sugar transporters. The semi-SWEET domain is composed of a simple 1-3-2 triple transmembrane helix bundle (THB), whereas the SWEET domain consists of two semi-SWEET domains linked by a transmembrane helix [ 15 ] ( Figure 2 A).…”

“…The semi-SWEET domain is composed of a simple 1-3-2 triple transmembrane helix bundle (THB), whereas the SWEET domain consists of two semi-SWEET domains linked by a transmembrane helix [ 15 ] ( Figure 2 A). Recently, Medrano-Soto et al proposed that the MPC belongs to the transporter-opsin-G protein-coupled receptor (TOG) superfamily with seven putative TMSs arranged in a 3+1+3 topology [ 14 ]. According to these authors, the MPC1 and MPC2 subunits might have originated from duplication of an MPC precursor, composed of four transmembrane segments, which would have lost its N-terminal transmembrane segment.…”

The Transporter Classification Database (TCDB): 2021 update

“…ultra-superfamilies or super-superfamilies including two or more superfamilies). We have found evidence for such higher-order relationships, for example, between the family NicO (TC# 2.A.113), a member of the LysE superfamily, and the family NiCoT (TC# 2.A.52), a member of the TOG superfamily ( 32 ). Such relationships may arise because of addition to or subtraction from TMSs in a repeat unit.…”

“…The Transporter/Opsin/G protein-coupled receptor (TOG) Superfamily has recently been expanded to include twelve families, and surprisingly, not all of the member families are typical transporters ( 32 ). They include light-dependent integral membrane chaperone proteins, photoreceptors and G-protein receptors.…”

Sequence Features of Mitochondrial Transporter Protein Families

“…MPCs have been predicted to harbor 2-3 transmembrane helices (TMHs) [31,32,35]. Interestingly, they are unrelated to SLC25 carriers and instead have been shown to be homologous to the 3-TMH repeating element in SWEET ("Sugars will eventually be exported transporters") transporters [36,37], which show a 3+1+3 TMH architecture [38,39]. Proteins from the SWEET family also exist as homodimers of half-transporters encompassing the 3-TMH repeat, called SemiSWEET [38,40].…”