2.A.18 The Amino Acid/Auxin Permease (AAAP) Family
The AAAP family includes hundreds of proteins from plants, animals, yeast and fungi. Individual permeases of the AAAP family transport auxin (indole-3-acetic acid), a single amino acid or multiple amino acids. Some of these permeases exhibit very broad specificities transporting all twenty amino acids naturally found in proteins. Some also transport D-amino acids. There are 7 AAAP paralogues in Saccharomyces cerevisiae, at least 9 in Arabidopsis thaliana and at least 5 in Caenorhabditis elegans. Six AAPs in A. thaliana transport neutral and charged amino acids with varying specificities and affinities (Fischer et al., 2002). All transport neutral amino acids and some acidic amino acids, always with just one proton. AAP3 and AAP5 are the only ones transporting basic amino acids, and only AAP6 transports aspartate (Fischer et al., 2002).
AAAP family proteins, all from eukaryotes, vary from 376 to 713 amino acyl residues in length, but most are of 400-500 residues. Most of the size variation occurs as a result of the presence of long N-terminal hydrophilic extensions in some of the proteins. Some of the yeast proteins are particularly long. Variation in the loops and the C-termini also occurs. These proteins exhibit 11 (or 10) putative transmembrane α-helical spanners (TMSs). One homologue, AAP1 of A. thaliana (TC #2.A.18.2.1), has 11 established TMSs (Chang and Bush, 1997). Members of the family have been tabulated (sometimes with functions) for foxtail millet (Setaria italica) (Yang et al. 2021).
Among animal AAAP family members are numerous growth regulating System A and System N isoforms, each exhibiting distinctive tissue and subcellular localizations. The different isoforms also exhibit different relative affinities for the amino acid substrates. Some catalyze H+ antiport and can function bidirectionally. Since Systems A are electrogenic although Systems N are not, the amino acid:cation stoichiometries may differ (Chaudhry et al., 2001, 2002; Varoqui et al., 2000).
Six auxin/amino acid permeases (AAAPs) from Arabidopsis mediate transport of a wide spectrum of amino acids (Fischer et al., 2002). AAAPs are distantly related to plasma membrane amino acid transport systems N and A and to vesicular transporters such as VGAT from mammals. Although capable of recognizing and transporting a wide spectrum of amino acids, individual AAAPs differ with respect to specificity. Apparent substrate affinities are influenced by structure and net charge and vary by three orders of magnitude (Fischer et al., 2002). AAAPs mediate cotransport of neutral amino acids with one proton, and uncharged forms of acidic and basic amino acids are cotransported with one proton. Since all AAAPs are differentially expressed, different tissues may be supplied with a different spectrum of amino acids.
Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought into cells by the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) subfamily, and the Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) subfamily, both members of the AAAP family. Members of both families can act as amino acid-stimulated receptors, or so-called 'transceptors,' connecting amino acids to mTORC1 activation (Fan and Goberdhan 2018). PATs and SNATs at the surfaces of multiple intracellular compartments are linked to the recruitment and activation of different pools of mTORC1. Late endosomes and lysosomes are mTORC1 regulatory hubs, but a Golgi-localized PAT is also required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity (Fan and Goberdhan 2018).
The generalized transport reaction catalyzed by the proteins of the AAAP family is:
Substrate (out) + nH+ (out) → Substrate (in) + nH+ (in)
This family belongs to the APC Superfamily.
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|Williams, L.E. and A.J. Miller. (2001). Transporters responsible for the uptake and partitioning of nitrogenous solutes. Annu. Rev. Plant Physiol. Plant Mol. Biol. 52: 659-688.|
|Wipf, D., U. Ludewig, M. Tegeder, D. Rentsch, W. Koch, and W.B. Frommer. (2002). Conservation of amino acid transporters in fungi, plants and animals. Trends Biochem. Sci. 27: 139-147. |
|Wu, H., P. Hu, Y. Xu, C. Xiao, Z. Chen, X. Liu, J. Jia, and H. Xu. (2021). Phloem Delivery of Fludioxonil by Plant Amino Acid Transporter-Mediated Polysuccinimide Nanocarriers for Controlling Fusarium Wilt in Banana. J Agric Food Chem 69: 2668-2678.|
|Yang, Y., Y. Chai, J. Liu, J. Zheng, Z. Zhao, A. Amo, C. Cui, Q. Lu, L. Chen, and Y.G. Hu. (2021). Amino acid transporter (AAT) gene family in foxtail millet (Setaria italica L.): widespread family expansion, functional differentiation, roles in quality formation and response to abiotic stresses. BMC Genomics 22: 519.|
|Yao, D., B. Mackenzie, H. Ming, H. Varoqui, H. Zhu, M.A. Hediger, and J.D. Erickson. (2000). A novel system A isoform mediating Na+/neutral amino acid cotransport. J. Biol. Chem. 275: 22790-22797.|
|Young, G.B., D.L. Jack, D.W. Smith, and M.H. Saier, Jr. (1999). The amino acid/auxin:proton symport permease family. Biochim. Biophys. Acta 1415: 306-322.|
|Zhang, Z. and C. Grewer. (2007). The sodium-coupled neutral amino acid transporter SNAT2 mediates an anion leak conductance that is differentially inhibited by transported substrates. Biophys. J. 92: 2621-2632.|
|Zhang, Z., C.B. Zander, and C. Grewer. (2011). The C-terminal domain of the neutral amino acid transporter SNAT2 regulates transport activity through voltage-dependent processes. Biochem. J. 434: 287-296.|
|Zhao, L., X. Ji, X. Zhang, L. Li, Y. Jin, and W. Liu. (2018). FLCN is a novel Rab11A-interacting protein and is involved in the Rab11A-mediated recycling transport. J Cell Sci. [Epub: Ahead of Print]|
Auxin:H+ symporter (auxin influx), AUX, AUX1, AUX-1, or LAX (Reinhardt et al., 2003; Carraro et al., 2012). In the PILS (Pin-like) family; members are located in the endoplasmic reticular membrane (Balzan et al. 2014). Expression patterns of PILS family members have been studied (Mohanta et al. 2015). Involved in determination of first pod height (FPH), a quantitative trait in soybean [Glycine max (L.) Merr.] that affects mechanized harvesting (Jiang et al. 2018). Auxin regulates several aspects of plant growth and development and is predominantly synthesized in the shoot apex and developing leaf primordia and from there it is transported to the target tissues e.g. roots. It is essential for root development, root gravitropism, root hair development, vascular patterning, seed germination, apical hook formation, leaf morphogenesis, phyllotactic patterning, female gametophyte development embryo development and the regulation of plant responses to abiotic stresses (Swarup and Bhosale 2019).
Aux-1 of Arabidopsis thaliana
Putative amino acid transporter, AAT
AAT of Homo sapiens (Q8NE00)
Putative amino acid transporter, AAT
AAT of Entamoeba histolytica (C4LSN3)
Putative amino acid transporter, AAT
AAT of Giardia intestinalis (C6LXJ3)
AAAP homologue of Tetrahymena thermophilus
|2.A.18.2.1||General amino acid permease 1, AAP1 (transports most neutral and acidic amino acids but not aspartate or the basic amino acids) ||Plants ||AAP1 of Arabidopsis thaliana |
|2.A.18.2.10||Probable amino acid permease 7 (Amino acid transporter AAP7)||Plants||AAP7 of Arabidopsis thaliana |
Lysine/histidine transporter, LHT1, of 446 aas and 10 or 11 TMSs (Chen and Bush 1997). It has been reported to be an amino acid-proton symporter with a
broad specificity for histidine, lysine, glutamic acid, alanine, serine,
proline and glycine 90. It is involved in both apoplastic transport of amino
acids in leaves and their uptake by roots (Hirner et al. 2006; Svennerstam et al. 2007; Svennerstam et al. 2008). There is some controversy about which amino acids it can take up, but it may play a role in fungicide uptake (Wu et al. 2021).
LHT1 of Arabidopsis thaliana
|2.A.18.2.3||General amino acid transporter 3, AAP3 (transports all neutral, acidic and basic amino acids tested)||Plants||AAP3 of Arabidopsis thaliana|
|2.A.18.2.4||General amino acid transporter 6, AAP6 (transports all neutral and acidic amino acids tested including aspartate, and basic amino acids are transported with low affinity) (Okumoto et al., 2002)||Plants||AAP6 of Arabidopsis thaliana|
General amino acid transporter 8, AAP8 (transports all amino acids, but the basic amino acids are transported
with low affinity (Okumoto et al., 2002)). It is a proton symporter with broad specificity for acidic and neutral amino acids, and is important for seed development (Schmidt et al. 2007) as well as phloem loading with amino acids (Santiago and Tegeder 2016). It contributes (as does AAP1) to grain quality (Yang et al. 2021).
AAP8 of Arabidopsis thaliana
Lysine-Histidine Transporter-7 (LHT7) found in mature pollen (Bock et al., 2006) (most like 2.A.18.2.2; 30% identity)
LHT7 of Arabidopsis thaliana (Q84WE9)
|2.A.18.2.7||Amino acid permease 2 (Amino acid transporter AAP2)||Plants||AAP2 of Arabidopsis thaliana |
|2.A.18.2.8||Lysine histidine transporter-like 8 (Amino acid transporter-like protein 1)||Plants||AATL1 of Arabidopsis thaliana |
Lysine/histidine transporter 2 (AtLHT2) (Amino acid transporter-like protein 2). There are 15 LHTs in maize (Zea mays) (Rabby et al. 2022).
LHT2 of Arabidopsis thaliana
|2.A.18.3.1||Proline permease 1 ||Plants ||Prt1 of Arabidopsis thaliana|
|2.A.18.3.2||Proline/GABA/glycine betaine permease, ProT1||Plants||ProT1 of Lycopersicon esculentum|
Proline transporter, ProT2 of 439 aas and 11 TMSs. SlProT1 and SlProT2 genes seem to be more active than the others in response to abiotic stress conditions, but all are active (Akbudak and Filiz 2020).
ProT2 of Solanum lycopersicum (Tomato) (Lycopersicon esculentum)
|2.A.18.4.1||Neutral amino acid permease ||Fungi ||AAP1 of Neurospora crassa |
|2.A.18.4.2||Aromatic and neutral amino acid permease, PcMtr (Trip et al., 2004)||Fungi||PcMtr of Penicillium chrysogenum (AAT45727)|
Vesicular γ-aminobutyric acid (GABA) and glycine transporter (Aubrey et al., 2007)
UNC-47 of Caenorhabditis elegans
|2.A.18.5.2||The vacuolar amino acid transporter AVT1 (catalyzes uptake into yeast vacuoles of large neutral amino acids including tyr, gln, asn, leu and ile)||Yeast||AVT1 of Saccharomyces cerevisiae |
The vacuolar GABA and glycine uptake transporter, VGAT. Also called "vesicular inhibitory amino acid transporter" (VIAAT); it is a 2Cl-/γ-aminobutyrate or glycine co-transporter in synaptic vesicles (Juge et al., 2009). GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype (Aubrey et al., 2007).
VGAT of Mus musculus (O35633)
Vesicular inhibitory amino acid transporter (GABA and glycine transporter; Solute carrier family 32 member 1; Vesicular GABA transporter; VGAT; hVIAAT). Probably functions by GABA:H+ antiport (Farsi et al. 2016). It localizes to the distal kidney tubule epithelia, especially in the inner medulla and basal portions of the lateral plasma membranes, but not in vesicles or vacuoles (Sakaew et al. 2018).
SLC32A1 of Homo sapiens
The aggression-related transporter, CG13646 of 527 aas and 11 TMSs. Reduction in expression of CG13646 by
approximately half leads to a hyperaggressive phenotype partially resembling that seen in Bully
flies (Chowdhury et al. 2017). Members of this family are involved in glutamine/glutamate and GABA cycles of metabolism in
excitatory and inhibitory nerve terminals.
CG13646 of Drosophila melanogaster
|2.A.18.6.1||Neuronal glutamine (System A-like) transporter, GlnT ||Animals ||GlnT of Rattus norvegicus (Q9JM15)|
Vacuolar broad specificity amino acid transporter 5 Avt5. Transports histidine, gluatmate, tyrosine, arginine, lysine and serine (Chardwiriyapreecha et al., 2010).
Avt5 of Saccharomyces cerevisiae (P38176)
SLC38 member 6, SNAT6. Na+-dependent synaptic vesicle amino acid release porter (Gasnier, 2004) (transports amino acids,glutamate, glutamine, glycine and γ-amino butyric acid (GABA)). It seems to be the only glutamine transporter in the brain, being present in excitatory neurons, particularly at the synapses (Bagchi et al. 2014). Glutamine uptake via SNAT6 and caveolin (TC# 8.A.26) regulates the glutamine-glutamate cycle (Gandasi et al. 2021). It exhibits a high degree of specificity for glutamine and glutamate, and the presence of these substrates enables formation of SNAT6-caveolin complexes that aid in sodium-dependent trafficking. Interacting partners of SNAT6 include CTP synthase 2 (CTPs2), phosphate-activated glutaminase (Pag; Kvamme et al. 2001), and glutamate metabotropic receptor 2 (Grm2; TC# 9.A.14.7.9) (Gandasi et al. 2021).
SLC38A6 of Homo sapiens
Solute carrier family 38, member 8, SLC38A8, expressed only in the eye. This protein is probably a Na+/H+-dependent amino acid (glutamine) transporter which when defective, gives rise to foveal hypoplasia associated with congenital nystagmus and reduced visual acuity, FHONDA (Perez et al. 2014). SLC38A8 mutations exhibit arrest of retinal development at an early stage, resulting in a poorly developed retina with a severe phenotype (Kuht et al. 2020).
SLC38A8 of Homo sapiens
Sodium-coupled neutral amino acid transporter 7, SNAT7. Transports L-glutamine in excitatory neurons 9but not astrocytes) as the preferred substrate, particularly at synapses, but also transports L-glutamate and other amino
acids with polar side chains such as L-histidine and L-alanine (Hägglund et al. 2011).
SLC38A7 of Homo sapiens
Sodium-coupled neutral amino acid transporter 1 (Amino acid transporter A1; SLC38A1; SNAT1; N-system amino acid transporter 2; Solute carrier family 38 member 1; System A amino acid transporter 1; System N amino acid transporter 1). When overexpressed, it causes Rett syndrome (RTT), an autism spectrum disorder caused by
loss-of-function mutations in the gene encoding MeCP2, an epigenetic
modulator (transcriptional repressor) of SLC38A1,
which encodes a major glutamine transporter (SNAT1). Because glutamine is mainly
metabolized in the mitochondria where it is used as an energy substrate
and a precursor for glutamate production, SNAT1
overexpression in MeCP2-deficient microglia impairs glutamine
homeostasis, resulting in mitochondrial dysfunction as well as
microglial neurotoxicity because of glutamate overproduction (Perez et al. 2014).
SLC38A1 of Homo sapiens
Neutral amino acid transporter 5 (Solute carrier family 38 member 5, SNAT5) (System N transporter 2, SN2). Transports glutamine, histidine and glycine as well as other amino acids. Present in glial cells where it probably functions in neurotransmitter clearance from synapses (Rodríguez et al. 2014). May also take up cisplatin (Girardi et al. 2020).
SLC38A5 of Homo sapiens
Sodium-coupled amino acid transporter 10, SNAT10. Expressed in several endocrine organs (Sundberg et al. 2008). Transports glutamine, glutamate and aspartate in neuronal and astrocytic cells (Hellsten et al. 2017).
SLC38A10 of Homo sapiens
|2.A.18.6.17||Sodium-coupled neutral amino acid transporter 4 (Amino acid transporter A3) (Na(+)-coupled neutral amino acid transporter 4) (Solute carrier family 38 member 4) (System A amino acid transporter 3) (System N amino acid transporter 3)||Animals||SLC38A4 of Homo sapiens|
Putative sodium-coupled neutral amino acid transporter 11, SNAT11 (Forde et al. 2014).
SLC38A11 of Homo sapiens
|2.A.18.6.19||Vacuolar amino acid transporter 7||Fungi||AVT7 of Saccharomyces cerevisiae |
Liver histidine and glutamine specific system N-like, Na+-dependent amino acid transporter, mNAT. Also called SNAT3. SNAT3 trafficking occurs in a dynamin-independent manner and is influenced by caveolin (Balkrishna et al., 2010).
mNAT of Mus musculus (Q9JLL8)
|2.A.18.6.20||Vacuolar amino acid transporter 2||Fungi||AVT2 of Saccharomyces cerevisiae |
Amino acid transporter 10 of 490 aas and 12 TMSs, AATP10 or AAT4.1. Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).
AATP10 of Trypanosoma brucei
Amino acid transporter 17.2, AAT17.2 of 494 aas and 11 TMSs. Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).
AAT17.2 of Trypanosoma brucei
Probable amino acid transporter of 378 aas and 10 TMSs.
aa transporter of Red seabream iridovirus
Uncharacterized putative amino acid transporter of 574 aas and 12 TMSs
UP of Entamoeba histolytica
System N1, SNAT3 [glutamine/histidine/asparagine/alanine]:[Na+ + H+] sym/antiporter (1 aa + 2 Na+ cotransported against 1 H+ antiported out) (probable orthologue of mNAT). Li+ can substitute for Na+; system N1 can function bidirectionally. SNAT3 is a primarily a glutamine transporter required for amino acid homeostasis. Loss cannot be compensated,
suggesting that this transporter is a major route of glutamine transport
in the liver, brain, and kidney (Chan et al. 2015). Biallelic variants of SLC38A3 cause epileptic encephalopathy (Marafi et al. 2021).
SLC38A3 of Homo sapiens
Plasma membrane System A-like neutral amino acid transporter, SA1, SAT2 or SNAT2 (transports small, neutral aliphatic amino acids including α-(methylamino)isobutyrate, mAIB with Na+ (1:1 stoichiometry; Km = 200-500 μM)). Asparagine 82 controls the interaction of Na+ with the transporter (Zhang and Grewer, 2007). The C-terminal domain regulates transport activity through a voltage-dependent process (Zhang et al., 2011). An 11 TMS topology has been experimentally demonstrated (Ge et al. 2018).
SAT2 of Rattus norvegicus (Q9JHE5)
Na+-dependent system A-like transporter, SLC38A2, System A2 or ATA2, SAT2, SNAT2, transports neutral amino acids with decreasing affinity in the order: MeAIB, Ala, Gly, Ser, Pro, Met, Asn, Gln, Thr, Leu and Phe. The neuronal system A2 has been reported to transport Asn and Gln with higher affinity than for other neutral amino acids. ATA2 is stored in the Golgi network and released by insulin stimulus in adipocytes (Hatanaka et al., 2006a). Its levels are regulated by ubiquitin ligase, Nedd4-2, which causes endocytotic sequestration and proteosomal degradation (Hatanaka et al., 2006b). SNAT2 also functions as a mammalian amino acid transceptor (transporter/receptor), acting in an autoregulatory gene expression pathway (Hyde et al., 2007). It also mediates an anion leak conductance that is differentially inhibited by transported substrates (Zhang and Grewer, 2007). It also transports homocysteine (Tsitsiou et al., 2009). It and other SLC proteins belonging to different families and subcellular compartments are subject to induced degradation by heterobifunctional ligands (Bensimon et al. 2020), thus allowing chemical control of transporter protein abundance.
SLC38A2 of Homo sapiens
|2.A.18.6.6||The vacuolar amino acid transporter, AVT6 (catalyzes efflux from yeast vacuoles of acidic amino acids, Asp and Glu)||Yeast||AVT6 of Saccharomyces cerevisiae (P40074)|
The Na-dependent alanine/α-(methylamino) isobutyric acid-transporting system A, ATA3 or SNAT4. Transports most neutral short chain amino acids electrogenically. Present only in liver and skeletal muscle. 47% and 57% identical to ATA1 and ATA2, respectively. A 10TMS topology [with N-and C-termini outside and a large N-glycosylated, extracellular loop domain (residues 242-335)] has been established (Shi et al., 2011). (Km(ALA)= 4mM; Na+:Ala= 1:1) (Sugawara et al., 2000)
ATA3 of Rattus norvegicus (Q9EQ25)
Second subtype of system N; glutamine transporter, SN2. Prevalent in liver, but detectable in other tissues. Amino acid uptake is coupled to Na+ influx and H+ efflux (Nakanishi et al., 2001)
SN2 of Rattus norvegicus (Q91XR7)
|2.A.18.6.9||Arginine-specific transporter, AAP3 (KM (Arg) = 2μM)||Protozoa||AAP3 of Leishmania donovani (Q86G79)|
|2.A.18.7.1||The vacuolar amino acid transporter, AVT3 (catalyzes efflux from yeast vacuoles of large neutral amino acids such as tyr, gln, asn, leu and ile)||Yeast||AVT3 of Saccharomyces cerevisiae |
|2.A.18.7.2||Vacuolar amino acid transporter 4||Fungi||AVT4 of Saccharomyces cerevisiae |
Vacuolar amino acid transporter 3, Avt3. Catalyzes efflux from vacuoles of large hydrophobic and hydrophilic neutral amino acids, and is required for sporulation.
Avt3 of Schizosaccharomyces pombe
Proline/alanine transporter of 488 aas and 10 TMSs, AAP24. The first 18 amino acids of the negatively charged N-terminal LdAAP24
tail are required for alanine transport and may facilitate the
electrostatic interactions of the entire negatively charged N-terminal
tail with the positively charged internal loops in the transmembrane
domain. This mechanism may underlie regulation of
substrate flux rate for this and other transporters (Schlisselberg et al. 2015).
AAP24 of Leishmania infantum
Amino acid transporter-6, AAT6 of 488 aas and 11 TMSs. Transports neutral amino acids and the drug, eﬂornithine (Schmidt et al. 2018). Eflornithine is used in combination with nifurtimox to combat T. brucei disease, and resistance to eflornithine is caused by the deletion or mutation of TbAAT6 which transports eflornithine into the cell (Kasozi et al. 2022).
AAT6 of Trypanosoma brucei
The electrogenic, proton-dependent amino acid:H+ symporter, PAT1 or LYAAT-1 (Slc36A1). Catalyzes uptake of L-Gly, L-Ala, L-Pro, γ-amino butyrate, and short chain D-amino acids such as proline and hydroxyproline with an aa/ H+ ratio of 1:1 (found in lysosomes) In humans, this is the iminoglycinuria protein (Boll et al., 2004; Miyauchi et al., 2005; Broer, 2008). A disulfide bridge is essential for transport function (Dorn et al., 2009). Transports taurine and β-alanine by H+ symport with low affinity and high capacity across the intestinal brush boarder membrane (Anderson et al., 2009). Exhibits low affinity (Km= 1-10 mM) and transports amino acid-based drugs used to treat epilepsy, schizophrenia, bacterial infections, hyperglycemia and cancer (Thwaites and Anderson, 2011). It is regulated by the Birt-Hogg-Dubé (BHD) syndrome related protein FLCN that has been implicated in the vesicular trafficking processes by interacting with several Rab family GTPases. FLCN binds via its C-terminal DENN-like domain to the recycling transport regulator, Rab11A, and promoted the loading of PAT1 on Rab11A (Zhao et al. 2018).
mPAT1 of Mus musculus (Q8K4D3)
Electrogenic, proton-coupled, amino acid symporter 2 (PAT2; Tramdorin-1; SLC36A2) (transports small amino acids: glycine, alanine and proline; found in the ER, not in lysosomes, of neuronal cells in the brain and spinal cord; it can catalyze bidirectional transport depending on the driving force) (Boll et al., 2004; Rubio-Aliaga et al., 2004). SLC36A2 is expressed at the apical surface of the human renal proximal tubule where it functions in the reabsorption of glycine, proline, hydroxyproline and amino acid derivatives with narrower substrate selectivity and higher affinity (Km 0.1-0.7 mM) than SLC36A1. Mutations in SLC36A2 lead to hyperglycinuria and iminoglycinuria.
PAT2 of Mus musculus (AAH44800)
|2.A.18.8.3||Amino acid transporter (low capacity, high affinity) and amino acid-dependent signal transduction protein, Pathetic (Path) (Goberdhan et al., 2005)||Animals||Path of Drosophila melanogaster (Q9VT04)|
H+-coupled amino acid transporter-3 (SLC36A3). SLC36A3 is expressed only in testes and has no known function (Thwaites and Anderson 2011).
SLC36A3 of Homo sapiens
H+-coupled amino acid transporter-4; SLC36A4. SLC36A4 is widely distributed and has high-affinity (Km = 2-3 µM) for proline and tryptophan (Thwaites and Anderson 2011). Gut microbiota-derived butyrate may have therapeutic potential in affective disorders characterized by either aberrant serotonergic activity or neuroinflammation due to its role in rescuing the oxidative stress-induced perturbations of tryptophan transport (Rode et al. 2021).
SLC36A4 of Homo sapiens
|2.A.18.8.6||Proton-coupled amino acid transporter 2 (Proton/amino acid transporter 2) (Solute carrier family 36 member 2) (Tramdorin-1)||Animals||SLC36A2 of Homo sapiens|
Proton-coupled amino acid transporter 1 (Proton/amino acid transporter 1) (hPAT1 or LYAAT-1) (Solute carrier family 36 member 1). SLC36A1 is expressed at the luminal surface of the small intestine but
is also commonly found in lysosomes in many cell types (including
neurons), suggesting that it is a multipurpose carrier with distinct roles in different cells including absorption in the
small intestine and as an efflux pathway following intralysosomal protein breakdown. SLC36A1 has a relatively low affinity (Km = 1-10 mM) for its
substrates, which include zwitterionic amino and imino acids,
heterocyclic amino acids and amino acid-based drugs and derivatives used
experimentally and/or clinically to treat epilepsy, schizophrenia,
bacterial infections, hyperglycaemia and cancer (Thwaites and Anderson 2011). hPAT1 transports the pyridine alkaloids, arecaidine, guvacine and isoguvacine, across the apical
membrane of enterocytes and might be responsible for the
intestinal absorption of these drug candidates (Voigt et al. 2013).
SLC36A1 of Homo sapiens
|2.A.18.8.8||Putative amino acid permease F59B2.2||Worm||F59B2.2 of Caenorhabditis elegans|
Small, semipolar, amino acid (Ser, Pro, Cys, Ala and Gly) uniporter, NEAAT of 463 aas and 9 - 12 TMSs. It catalyzes electroneutral bidirectional amino acid exchange is response to amino acid concentration gradients (Feng et al. 2019). This transporter is present in thebacteriocyte (symbiosome) membrane which houses the symbiotic bacteria that produce the essential amino acids for the aphid.
NEAAT of Acyrthosiphon pisum (Pea aphid)
Na+-coupled high affinity, lysosomal arginine transporter and sensor, SLC38A9 (561aas; 11 TMSs) (Gu et al. 2017). Also transports many other amino acids with low affinity and specificity (Rebsamen et al. 2015). The rapamycin complex 1 (mTORC1) protein kinase is
a master growth regulator that responds to multiple environmental cues.
Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar ATPase-dependent fashion, the translocation of mTORC1 to the
lysosomal surface, where it interacts with its activator Rheb. Wang et al. 2015 showed that lysosomal SLC38A9
interacts with Rag GTPases and Ragulator
in an amino acid-sensitive fashion. SLC38A9 transports arginine, and loss of SLC38A9 represses mTORC1 activation
by amino acids, particularly arginine. Overexpression of SLC38A9 or
just its Ragulator-binding domain makes mTORC1 signaling insensitive to
amino acid starvation but not to Rag activity. Thus, SLC38A9 functions
upstream of the Rag GTPases and is probably the
arginine sensor for the mTORC1 pathway. Jung et al. 2015 confirmed SLC38A9 to be a Rag-Ragulator complex member, transducing amino acid availability to
mTORC1. Lysosomal cholesterol activates TORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (Castellano et al. 2017). The Niemann-Pick C1 (NPC1) protein (TC# 2.A.6.6.1), which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function (Castellano et al. 2017). Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state (Shen and Sabatini 2018). Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Thus, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency.
SLC38A9 of Homo sapiens
SLC38A9 of 549 aas and 111 TMSs. The crystal structure of this lysosomal transporter with arginine bound in the inward facing conformation has been solved (Lei et al. 2018). The bound arginine was locked in a transitional state stabilized by TMS1, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TMS1, and mutations in this motif abolished arginine transport (Lei et al. 2018).
SLC38A9 of Danio rerio (Zebrafish) (Brachydanio rerio)