2.A.86 The Autoinducer-2 Exporter (AI-2E) Family (formerly the PerM Family, TC #9.B.22) The AI-2E family (UPF0118) is a large family of prokaryotic proteins derived from a variety of bacteria and archaea. Those examined are about 350 residues in length, and the couple that have been examined exhibit 7 putative TMSs (Rettner and Saier, 2010). E. coli, B. subtilis and several other prokaryotes have multiple paralogues encoded within their genomes. Herzberg et al. (2006) have presented strong evidence for a role of a AI-2E family homologue, YdgG (renamed TqsA) is an exporter of the E. coli autoinducer-2 (AI-2) (Camilli and Bassler, 2006; Chen et al., 2002). AT-2 is a proposed signalling molecule for interspecies communication in bacteria. It is a furanosyl borate diester (Chen et al., 2002). It is induced in Bacillus subtilis by exposure to rice seedlings (Xie et al. 2015). AI-2, a universal molecule for both intra- and inter-species communication, is involved in the regulation of biofilm formation, virulence, motility, chemotaxis, and antibiotic resistance. (Khera et al. 2022). More recently, it has been reported that this family includes a member of the UPF0118 family (which was the former designation for the AI-2E family), and this transmembrane protein with 7 TMSs, exhibits reversible pH-dependent Na⁺ or Li⁺/H⁺ antiport activity. Phylogenetic analyses were reported (Dong et al. 2017). Thus, it appears that different members of the family may have very different transport functions. Cryo-EM structures of two pentameric autoinducer-2 exporter from E. coli (TqsA (TC# 2.A.86.1.4) and YdiK (TC# 2.A.86.2.1) revealed the probable transport mechanism (Khera et al. 2022). Each of the 5 subunits is believed to be a functional unit, and an elevator-type mechanism has been suggested. The transport reactions catalyzed by membeers of the AI-2E family are: AI-2 (in) ⇌ AI-2 (out) Na⁺ or Li⁺ (out) + H⁺ (in) → Na⁺ or Li⁺ (in) + H⁺ (out)
References:
Besse A., Peduzzi J., Rebuffat S. and Carre-Mlouka A. (2015). Antimicrobial peptides and proteins in the face of extremes: Lessons from archaeocins. Biochimie. 118:344-55.
Camilli, A. and Bassler, B.L. (2006). Bacterial small-molecule signaling pathways. Science 311: 1113-1116.
Chen, X., S. Schauder, N. Potier, A. Van Dorsselaer, I. Pelczer, B.L. Bassler, and F.M. Hughson. (2002). Structural identification of a bacterial quorum-sensing signal containing boron. Nature 415: 488-489.
Dong, P., L. Wang, N. Song, L. Yang, J. Chen, M. Yan, H. Chen, R. Zhang, J. Li, H. Abdel-Motaal, and J. Jiang. (2017). A UPF0118 family protein with uncharacterized function from the moderate halophile Halobacillus andaensis represents a novel class of Na(Li)/H antiporter. Sci Rep 7: 45936.
Eichenberger, P., S.T. Jensen, E.M. Conlon, C. van Ooij, J. Silvaggi, J.E. González-Pastor, M. Fujita, S. Ben-Yehuda, P. Stragier, J.S. Liu, and R. Losick. (2003). The sigmaE regulon and the identification of additional sporulation genes in Bacillus subtilis. J. Mol. Biol. 327: 945-972.
Herzberg, M., I.K. Kaye, W. Peti, and T.K. Wood. (2006). YdgG (TqsA) controls biofilm formation in Escherichia coli K-12 through autoinducer 2 transport. J. Bacteriol. 188: 587-598.
Khera, R., A.R. Mehdipour, J.R. Bolla, J. Kahnt, S. Welsch, U. Ermler, C. Muenke, C.V. Robinson, G. Hummer, H. Xie, and H. Michel. (2022). Cryo-EM structures of pentameric autoinducer-2 exporter from Escherichia coli reveal its transport mechanism. EMBO. J. e109990. [Epub: Ahead of Print]
Kociolek, L.K., D.N. Gerding, D.W. Hecht, and E.A. Ozer. (2018). Comparative genomics analysis of Clostridium difficile epidemic strain DH/NAP11/106. Microbes Infect 20: 245-253.
Nobre, L.S., F. Al-Shahrour, J. Dopazo, and L.M. Saraiva. (2009). Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli. Microbiology 155: 813-824.
Poppleton, D.I., M. Duchateau, V. Hourdel, M. Matondo, J. Flechsler, A. Klingl, C. Beloin, and S. Gribaldo. (2017). Outer Membrane Proteome of A Diderm Firmicute of the Human Microbiome. Front Microbiol 8: 1215.
Ravcheev, D.A., M.S. Gel'fand, A.A. Mironov, and A.B. Rakhmaninova. (2002). [Purine regulon of γ-proteobacteria: a detailed description]. Genetika 38: 1203-1214.
Rettner, R.E. and M.H. Saier, Jr. (2010). The autoinducer-2 exporter superfamily. J. Mol. Microbiol. Biotechnol. 18: 195-205.
Shao, L., T. Xu, X. Zheng, D. Shao, H. Zhang, H. Chen, Z. Zhang, M. Yan, H. Abdel-Motaal, and J. Jiang. (2020). A novel three-TMH Na/H antiporter and the functional role of its oligomerization. J. Mol. Biol. 433: 166730. [Epub: Ahead of Print]
Turner, M.S. and J.D. Helmann. (2000). Mutations in multidrug efflux homologs, sugar isomerases, and antimicrobial biosynthesis genes differentially elevate activity of the σ^X and σ^W factors in Bacillus subtilis. J. Bacteriol. 182: 5202-5210.
Xie, S., H. Wu, L. Chen, H. Zang, Y. Xie, and X. Gao. (2015). Transcriptome profiling of Bacillus subtilis OKB105 in response to rice seedlings. BMC Microbiol 15: 21.
Examples:
TC#	Name	Organismal Type	Example
2.A.86.1.1	Putative permease, PerM, of 353 aas and 7 or 8 TMSs.	Bacteria and archaea	*PerM of E. coli* (P0AFI9)**

2.A.86.1.10	Uncharacterized protein of 502 aas and 8 TMSs	Red algae	UP of Galdieria sulphuraria

2.A.86.1.11	7 TMS permease which is encoded by a gene adjacent to a spore germination receptor (2.A.3.9.5) and an ABC exporter (TC# 3.A.1.147.2).	Firmicutes	Permease of Paenibacillus mucilaginosus

2.A.86.1.12	*Putative permease of 322 aas and 6 TMSs, HalU (Besse et al.* 2015).**		HalU of Halobacterium sp. (strain AS7092)

2.A.86.1.13	Uncharacterized protein of 361 aas and 7 TMSs in a 2 + 5 TMS arrangement.		UP of Entamoeba histolytica

2.A.86.1.14	*The sodium-lithium/proton antiporter; Na⁺ or Li⁺/H⁺ antiporter, UPF0118 or YtvI of 352 aas and 7 TMSs (Dong et al.* 2017).**		Na⁺ or Li⁺/H⁺ antiporter of Halobacillus andaensis

2.A.86.1.15	*YtvI putative porter, of 363 aas and 8-10 TMSs in a 3 + 1, 2 or 3 + 3 + 1 arrangement. It is involved in virulence (Kociolek et al.* 2018).**		YtvI of Peptoclostridium difficile (Clostridium difficile)

2.A.86.1.16	Uncharacterized protein of 373 aas and 8 TMSs. Its gene is adjacent to an OmpA-like porin, so these two proteins may function together to export a substrate across both membranes in this diderm firmicute. The gene on the other side of the gene for this porter is an M4 peptidase, PepSY with a single N-terminal TMS, so it may be a periplasmic or outer membrane associated enzyme (Poppleton et al. 2017).		UP of Veillonella parvula

2.A.86.1.2	Putative permease, YhhT (a member of the PurR purine regulon) with 7 TMSs in a 2 + 1 + 4 TMS arrangement.	Bacteria and archaea	*YhhT of E. coli* (P0AGM0)**

2.A.86.1.3	*Putative permease, Yct2, encoded near the cta* operon; of 385 aas and 7 or 8 TMSs in a 1 or 2 + 1 + 4 TMS arrangement.**	Bacteria and archaea	*Yct2 of Bacillus firmus* (spQ04454)**

2.A.86.1.4	Autoinducer-2 (AI-2; a furanosyl borate diester) exporter, TqsA (YdgG). It plays a role in biofilm formation (Nobre et al. 2009). Cryo-EM structures of two pentameric autoinducer-2 exporter from E. coli (TqsA (TC# 2.A.86.1.4) and YdiK (TC# 2.A.86.2.1) revealed the probable transport mechanism (Khera et al. 2022). Each of the 5 subunits is believed to be a functional unit, and an elevator-type mechanism has been suggested (Khera et al. 2022).	Bacteria	*TqsA of E. coli* (POAFS5)**

2.A.86.1.5	Permease (residues 1-380) fused to an ATP/GTP P-loop NTPase (AAA) superfamily domain (420-658) (Walker B motif; IstB-like)	Bacteria	*Fused permease-ATPase protein of Brucella abortus* (C9VRY8)**

2.A.86.1.6	Putative aldose-1-epimerase (N-terminus) fusion protein with a 7-8 TMS C-terminal transporter domain. It is a possible aldose transporter.	Bacteria	*Aldose-1-epimerase-transporter fusion protein of Micrococcus luteus* (D3LPG3)**

2.A.86.1.7	Rv0205 (UFP0118) protein (376 aas, 8 putative TMSs) (may function with a heme uptake transporter) (TC# 2.A.6.5.5)	Bacteria	*Rv0205 of Mycobacterium tuberculosis* (O53656)**

2.A.86.1.8	Putative transporter, YueF. Negatively regulates the sigW gene that encode the extra cytoplasmic sigma factor, sigma W, that activates genes which function in detoxification and the production of antimicrobial compounds (Turner and Helmann, 2000). SigW controls genes involved in transport and detoxification.	Bacteria	*YueF of Bacillus subtilis* (O32095)**

2.A.86.1.9	Sporulation protein, YtvI of 371 aas and 6 - 8 TMSs. It is expressed under sigma E control, and null mutants are defective in spore formation (Eichenberger et al. 2003)). In Clostridium difficile, the orthologous ytvI gene is a virulence gene (Kociolek et al. 2018).	Bacilli	YtvI of Bacillus subtilis

Examples:
TC#	Name	Organismal Type	Example
2.A.86.2.1	Purine regulon gene product, YdiK (under PurR control (Ravcheev et al., 2002)) YdiK is of 370 aas with 7 or 8 TMSs. Cryo-EM structures of two pentameric autoinducer-2 exporter from E. coli (TqsA (TC# 2.A.86.1.4) and YdiK (TC# 2.A.86.2.1)) revealed the probable transport mechanism (Khera et al. 2022). Each of the 5 subunits is believed to be a functional unit, and an elevator-type mechanism has been proposed (Khera et al. 2022)..	Bacteria	*YdiK of E. coli* (B1LE48)**

2.A.86.2.2	AI-2E homologue of 395 aas and 7 TMSs in a 2 + 1 + 3 + 1 TMS arrangement.	Proteobacteria	AI-2E homologue of Myxococcus xanthus

2.A.86.2.3	Putative transporter	Archaea	Putative transporter of Natronomonas pharaonis

Examples:
TC#	Name	Organismal Type	Example
2.A.86.3.1	Protein belonging to family UPF0118, NhaM, of 384 aas and 3 or 4 N-terrminal TMSs. Members of this family were functionally characterized as Na⁺, Li⁺, K⁺/H⁺ anitiporters by Shao et al. 2020, but the family was first identified by Dong et al. 2017. Shao et al. 2020 showed that a small region of 104 aas and 3 TMSs was sufficient for antiport activity following oligomerization. The N-terminal hydrophobic domain is the only one showing homology with other members of the family.		NhaM of Rhodopirellula maiorica

2.A.86.3.2	AI-2E transporter of 624 aas and ~8 TMSs in a 2 + 1 + 4 or 5 TMS arrangement, followed by a 220 residue C-terminal hydrophilic extension.		*Transporter of Pseudacidobacterium ailaaui* (wood decay metagenome)**

2.A.86.3.3	AI-2E family protein of 719 aas and 7 or 8 TMSs in a 2 or 3 + 1 + 4 TMS arrangement.		AI-2E protein of Methyloligella halotolerans

Examples:
TC#	Name	Organismal Type	Example
2.A.86.4.1	TMEM245 protein of 879 aas and ~ 15 - 17 TMSs in a 1 or 2 + 4 + 2 + 1 + 1 or 2 + 4 TMS arrangement. Possibly there last 5 or 6 TMSs are homologous to and a repeat of the first 5 or 6 TMSs with 2 or 3 TMSs in the middle of the protein.		TMEM245 of Homo sapiens

2.A.86.4.2	Uncharacterized protein of 627 aas and possibly 12 TMSs in a 6 + 6 TMS arrangement.		*UP of Arctium lappa* (great burdock)**

2.A.86.4.3	TMEM245 of 1189 aas and ~ 13 TMSs in an apparent 3 + 2 + 2 + 2 + 6 (2 + 4) TMS arrangement.		TMEM245 of Micractinium conductrix

2.A.86.4.4	TMEM245 of 446 aas and 8 TMSs in an apparent 2 + 4 + 1 + 1 TMS arrangement.		TMEM245 protein of Elysia marginata

2.A.86.4.5	Uncharacterized protein of 1096 aas and 12 or 13 TMSs in a 2 + 4 + 6 or 7 TMS arrangement.		UP of Plasmodium falciparum