2.A.59 The Arsenical Resistance-3 (ACR3) Family
Two proteins of the ACR3 family have been functionally characterized. These proteins are the ACR3 protein of Saccharomyces cerevisiae, also called the ARR3 protein (Wysocki et al., 1997), and the 'ArsB' protein of Bacillus subtilis (Sato and Kobayashi, 1998). The latter protein is not related to ArsB of E. coli. The former yeast protein is present in the plasma membrane and pumps arsenite and antimonite, but not arsenate, tellurite, cadmium or phenylarsine oxide out of the cell in response to the pmf. It uses a proton antiport mechanism to extrude the anions with low affinity (Maciaszczyk-Dziubinska et al., 2011). The Bacillus protein exports both arsenite and antimonite. The exact transport mechanism is not established. Bacillus Acr3 probably has a 10 TMS topology (Aaltonen and Silow, 2008).
ACR3 of S. cerevisiae is 404 amino acyl residues long and exhibits 10 putative transmembrane α-helical spanners (TMSs). Homologues are found in Mycobacterium tuberculosis (498 aas; gbZ80225), Archaeoglobus fulgidus (370 aas; gbAE001071), Methanobacterium thermoautotrophicum (365 aas; gbAE000865) and Synechocystis (383 aas; spP74311). Thus, members of the ACR3 family are found in bacteria, archaea and eukarya. Sequence similarity of several members of the Acr3 family with members of the bile acid:Na+ symporter (BASS) family (TC #2.A.28) is sufficient to establish homology. The ACR3 family belongs to the BART superfamily (Mansour et al., 2007). When an ACR3 protein functions with an ATPase, that ATPase is a member of the ArsA superfamily.
Bioinformatic analyses have revealed that some ACR3 porters are involved in operons together with ArsA-like ATPases, implying that some of these porters may be driven by ATP hydrolysis as primary active transporters (Castillo and Saier, 2010). This may occur in addition to or instead of the secondary active transport mechanism established for ACR3 members noted above. Homologous ATPases are found in families 3.A.4, 3.A.19 and 3.A.21 as well as 2.A.59. A region of the ABC ATPase (3.A.1.26.8; the ribose transporter) shows significant sequence similarity to the ArsA under 3.A.19.1.1 (28% identical; 49% similarity, 0 gaps, e-5) as revealed by TC Blast.
The generalized reaction catalyzed by members of the ACR3 family is:
Arsenite or antimonite (in) Arsenite or antimonite (out)
Plasma membrane ACR3 arsenite exporter (AsIII:H+ antiporter) (Wysocki et al., 1997). Catalyzes proton antiport with either arsenite or antimonite. Cys151 is essential for transport activity, while Cys90 and Cys169 are important in trafficking (Maciaszczyk-Dziubinska et al. 2013). Other residues important for folding, trafficking and/or activity have also been identified (Markowska et al. 2015). This protein has 10 TMSs with cytoplasmically oriented N- and C-termini, and a homology-based structural model of Acr3 using the crystal structure of the Yersinia frederiksenii homologue of the human bile acid sodium symporter, ASBT, has been constructed (Wawrzycka et al. 2016).
ACR3 of Saccharomyces cerevisiae
ACR3 of Shewanella oneidensis (Q8EJD3)
Acr3 of Pyrococcus furiosus (Q8U3B8)
The arsenite-specific exporter, Acr3/ArsA1/ArsA2. ArsA1 and ArsA2 are half sized ATPases (Fu et al., 2010).
The Acr3/ArsA1/ArsA2 arsenite exporter of Alkaliphilus metalliredigens
The arsenite-specific exporter, Acr3'/ArsA1'/ArsA2'. ArsA1' and ArsA2' are half sized ATPases (Fu et al., 2009; 2010)
The Acr3'/ArsA1'/ArsA2' arsenite exporter of Alkaliphilus metalliredigens
Aresenite (AsIII):H+ antiporter, Acr3-1; confers resistance to As(III) but not Sb(III) (antimonite) (Villadangos et al. 2012; Yang et al. 2012).
Acr3-1 of Corynebacterium glutamicum
Putative efflux pump (Acr3)
Acr3 of Sulfitobacter sp. NAS-14.1 (A3T1V5)
Acr3 homologue of unknown function (10 putative TMSs)
Acr3 of Chloroflexus aggregans (B8GAD2)