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1.A.11 The Ammonium Channel Transporter (Amt) Family

The proteins of the Amt family vary in size from 391 to 622 amino acyl residues and possess 11 (N-terminus out; most members) or 12 (N-terminus in) transmembrane α-helical spanners (TMSs). The E. coli AmtB is a trimer (Blakey et al., 2002). It appears to have dual functions, transporting NH4+ and regulating nitrogen metabolism by directly interacting with regulatory proteins such as the PII protein and its homologue, GlnK (Blauwkamp and Ninfa, 2003). amtB and glnK form an operon, and GlnK regulates the activity of AmtB. Homologues are probably ubiquitous. In Azospirillum brasilense, AmtB forms a ternary complex between AmtB, GlnZ and the nitrogenase regulatory enzyme DraG (Huergo et al., 2007). Eukaryotic AmtB homologues, in general, are larger than the prokaryotic proteins. Most functionally characterized members of the family are ammonium uptake transporters (Soupene et al., 2002d). Some, but not other Amt proteins also transport methylammonium (Andrade and Einsle, 2007; Musa-Aziz et al., 2009).  Detailed phylogenetic analyses of plant homologues have been published (von Wittgenstein et al. 2014).

The structures of the E. coli AmtB (1.35 Å) (Khademi et al., 2004) and the Archaeoglobus fulgidus Amt-1 (Andrade et al., 2005) have been determined. They were considered to be gas channels with two structurally similar halves that span the membrane with opposite polarity. There is a vestibule that recruits NH4+, a binding site for NH4+ or CH3-NH3+ and a 20 Å long hydrophobic channel that lowers the NH4+ pKa to below 6 using weak interactions with C-H hydrogen bond donors such as those provided by conserved histidines. Reconstitution of AmtB into vesicles led to the conclusion that it conducts uncharged NH3, releasing H+ on the outside (Soupene et al., 2002a,b,c). However, a more recent study (Fong et al., 2007) concludes that NH4+ in the transported species. Hall and Kustu (2011) showed that NH4+ transport does not require the two histidyl residues, H168 and H318, which can be replaced by acidic residues with retention of activity. Ortiz-Ramirez et al. (2011) have concluded that the bean Amt1 protein is an H+/NH4+ symporter.

The E. coli ammonium channel, AmtB, and the PII signal transduction protein, GlnK, constitute an ammonium sensory system that effectively couples the intracellular nitrogen regulation system to external changes in ammonium availability. Direct binding of GlnK to AmtB inactivates the channel, thereby controlling ammonium influx in response to the intracellular nitrogen status. The stoichiometry of the complex is 1:1 for AmtB:GlnK (Durand and Merrick, 2006). Only the fully deuridylylated form of GlnK co-purifies with AmtB. Interaction of GlnK with AmtB is dependent on ATP and is sensitive to 2-oxoglutarate. Thus in vivo association and dissociation of the complex might not only be dependent on the uridylylation status of GlnK but also on the intracellular pools of ATP and 2-oxoglutarate (Durand and Merrick, 2006).

The 11 TMSs (M1-M11) of AmtB form a right handed helical bundle around each channel. Residues from helices M1, M6, M7, M8 and M9 of one monomer interact with residues from helices M1, M2 and M3 of the neighboring subunit to form an interacting surface area of 2716 Å2. Polar aromatic residues (Y and W) comprise part of the membrane-aqueous phase interface. AMTs may use a conserved allosteric control mechanism to regulate ammonium flux, potentially using a gating mechanism that limits flux to protect against ammonium toxicity (Loque et al., 2009).

Amt proteins are homotrimers, in which each subunit contains a narrow pore through which substrate transport occurs. Two conserved histidyl residues in the pore of the E. coli AmtB are absolutely necessary for ammonia conductance. Crystal structures of variants confirmed that substitution of the histidine residues does not affect AmtB structure. In a subgroup of Amt proteins found only in fungi, one of the histidines is replaced by glutamate. The equivalent substitution in E. coli AmtB is partially active, and the structure of this variant suggests that the glutamate side chain can make similar interactions to those made by histidine (Javelle et al., 2006).  As expected for a channel, NH3 uniport appears to occur by energy-independent, non-concentrative, bidirectional diffusion (Soupene et al., 2002a; Loque et al., 2007), but NH4+ may be the true substrate (Fong et al., 2007).

Amt proteins facilitate ammonium ion transport across the membranes of plants, fungi, and bacteria.  On the basis of the structural data for E. coli AmtB, Wang et al. (2012) deduced the mechanism by which electrogenic transport occurs. Free energy calculations show that NH4+ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate may diffuse down the pore in the form of NH3, while the proton is cotransported through a highly conserved hydrogen-bonded His168-His318 pair. This constitutes a novel permeation mechanism that confers to the histidine dyad an essential mechanistic role that is equivalent to symport (Wang et al. 2012).  Thus these systems blur the boundary between channels and secondary carriers.

Plant AMTs have been reported to mediate electrogenic transport as noted above. Functional analysis of AMT2 from Arabidopsis (TC #1.A.11.2.2) expressed in yeast and oocytes suggests that NH4+ is the recruited substrate, but the uncharged form (NH3) is conducted (Neuhäuser et al., 2009). AMT2 partially co-localizes with electrogenic AMTs and conducts methylamine with low affinity. This transport mechanism may apply to other plant ammonium transporters and explains the different capacities of AMTs to accumulate ammonium in the plant cell.

A P(II) signal transduction protein, GlnK, is a regulator of transmembrane ammonia conductance by  AmtB in Escherichia coli. The complex formed between AmtB and inhibitory GlnK at 1.96-A resolution shows that the trimeric channel is blocked directly by GlnK. In response to intracellular nitrogen status, the ability of GlnK to block the channel is regulated by uridylylation/deuridylylation at Y51. ATP and Mg2+ augment the interaction of GlnK. The hydrolyzed product, adenosine 5'-diphosphate, orients the surface of GlnK for AmtB blockade. 2-Oxoglutarate diminishes AmtB/GlnK association (Gruswitz et al., 2007). MepB, in contrast to MepA and MepC, similarly appears to be the primary NH4+ transporter and serves as a regulator for nitrogen sensing in Fusarium fujikuroi (Teichert et al., 2007).

Many organisms from all major kingdoms of living organisms possess multiple homologues. Rhodobacter capsulatus has two Amt family homologues, AmtB and AmtY. The former, but not the latter, has been reported to be an NH4+ sensor as well as a NH3 transporter (Yakunin and Hallenbeck, 2002). Mep2 of Saccharomyces cerevisiae has been shown to function both as a transporter and as a sensor, generating a signal that regulates filamentous growth (pseudohyphal differentiation) in response to ammonium starvation (Lorenz and Heitman, 1998). This protein has an N-terminal, asparaginyl-linked glycosylated domain where only Asn-4 is glycosylated. Mep2, but not Mep1 or Mep3, has an extracytoplasmic N-terminus (Marini and André, 2000). This N-terminal domain is not required for either transport or sensing. Of the three S. cerevisiae Amt family paralogues, Mep2 exhibits higher affinity for NH4+ (1 μM) than Mep1 (10 μM), and Mep1 exhibits higher affinity than Mep3 (1 mM).

The Amt family includes the Rhesus (Rh) family of proteins, both erythroid (RhAG, RhD and RhCE) and non-erythroid (RhCG, RhBG and RhGK). In the mammalian kidney collecting duct, RhBG is in the basolateral membrane while RhCG is in the apical membrane. Basolateral anchoring of RhBG requires ankyrin-G (Lopez et al., 2005). It has been proposed that some of these proteins are CO2 channels, but this suggestion has not been substantiated (Soupene et al., 2002d).

Loque et al. (2007) have shown that the soluble, cytosolic C-terminus of Amt1.1 of Arabidopsis thaliana is an allosteric regulator. This domain is conserved between bacteria, fungi and plants. Mutations in this domain lead to loss of transport activity. The crystal structure of an Amt family member from Archaeoglobus fulgidus suggests that the C-terminal domain interacts physically with the cytosolic loops of the neighboring subunit. Phosphorylation of conserved sites in the C-terminal domain with conformational coupling between monomers may allow tight regulation of transport and sensing (Loque et al., 2007).

In Cryptococcus neoformans, Amt1 and Amt2 are low and high affinity ammonium permeases, respectively. AMT2 is transcriptionally induced in response to nitrogen limitation whereas AMT1 is constitutively expressed. Amt2 is required for the initiation of invasive growth of haploid cells under low nitrogen conditions and for the mating of wild type cells under the same conditions. It was proposed that Amt2 may be a new fungal ammonium sensor and an element of the signaling cascades that govern the mating of C. neoformans in response to environmental nutritional cues (Rutherford et al., 2007).

The C-terminal cytoplasmic domains allosterically activate adjacent channels in the trimeric structures of Amt channels. Mutations in helix 1 yield up to 100-fold lower affinity with 10-fold increased flux (Loqué et al., 2007; Loqué et al., 2009) in A. fulgidus (TC# 1.A.11.2.7). The A. thaliana protein, Amt1;1 (TC# 1.A.11.2.1), is phosphorylated on Thr460 giving rise to inhibition in response to high [NH3] (Lalonde et al., 2008; Lanquar et al., 2009; Yuan et al., 2007).

There is presently no direct evidence to support the idea that Rh proteins transport CO2/H2CO3. However, physiological studies in the green alga Chlamydomonas reinhardtii do suggest its Rh1 protein is involved in CO2 metabolism (Soupene et al., 2004). In addition, structural work on the Rh protein of Nitrosomonas europaea identified a CO2 binding site on the substrate conduction pathway (Andrade et al., 2005a). By analogy to the Amt proteins (transport of hydrated ammonia), some Rh proteins may transport H2CO3, but this is hypothetical.

Amt proteins appear to function as channel/carrier hybrids. Consistent with these proteins functioning as channels, structural studies indicate that there are no large overall conformational differences between substrate-free and substrate-complexed proteins. Andrade et al., 2005b did find evidence that TMS5 of Archaeoglobus fulgidus Amt-1 could move in a way that could be functionally significant. Genetic work (Inwood et al., 2009) suggests that such movement - an oscillation of TMS5 - may control the opening of both the entrance and exit to the AmtB conduction pore.  Furthermore, work conducted by (Fong et al., 2007) indicated that AmtB concentrates methylammonium. The movement of TMS5 during substrate transport and the ability to concentrate substrate are characteristics of a carrier-type transporter. Whether NH4+ dissociates as it goes through the channel with NH3 going through the pore and H+ taking another route is a separate question. Because the conduction pore is hydrophobic, a mechanism based on NH4+ dissociation to NH3 and H+ appears possible.

The transport of NH4+ is an active process as has been shown experimentally by several groups. By working with an AmtB mutant in a ΔglnA background, methylammonium was concentrated roughly 100-fold (Fong et al., 2007). Accumulation was prevented by CCCP and, thus, was dependent upon the proton motive force.

The X-ray structures have revealed that the pore of the Amt and Rh proteins is characterized by a hydrophobic portion about 12A long in which electronic density was observed in the crystallographic study of AmtB from Escherichia coli. This electronic density was initially only observed when crystals were grown in the presence of ammonium and was thus attributed to ammonia molecules. The Amt/Rh protein mechanism might involve the single-file diffusion of NH3 molecules. However, the pore could also be filled with water molecules. The possible presence of water molecules in the pore lumen calls for a reassessment of the notion that Amt/Rh proteins work as plain NH3 channels. Indeed, functional experiments on plant ammonium transporters and rhesus proteins suggest a variety of permeation mechanisms including the passive diffusion of NH3, the antiport of NH4+/H+, the transport of NH4+, or the cotransport of NH3/H+Lamoureux et al. (2010) discuss these mechanisms in light of functional and simulation studies on the AmtB transporter.

Note: The AMT family was previously given the TC# 2.A.49.

The generalized transport reactions catalyzed by members of the Amt family are suggested to be:

(1) NH4+ (out) ⇌ NH4+ (in)

[In E. coli, NH4+, rather than NH3, may be the substrate of AmtB, but controversy still exists (Fong et al., 2007; Ishikita and Knapp, 2007; Javelle et al., 2006). If NH4+ is transported, K+ possibly serves as a counter ion in an antiport process with K+ (Fong et al., 2007).]

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