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Nucleotide Sugar Transporters: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Maciej Wiktor.

Nucleotide sugars (NSs) serve as substrates for glycosylation reactions. The majority of these compounds are synthesized in the cytoplasm, whereas glycosylation occurs in the endoplasmic reticulum (ER) and Golgi lumens, where catalytic domains of glycosyltransferases (GTs) are located. Therefore, translocation of NS across the organelle membranes is a prerequisite. This process is thought to be mediated by a group of multi-transmembrane proteins from the SLC35 family, i.e., nucleotide sugar transporters (NSTs).

  • nucleotide sugar transporter
  • glycosylation
  • SLC35A1
  • SLC35A2
  • SLC35A3
  • SLC35C1
  • SLC35B4

1. Current State of Structural Studies on NSTs

The identification of genes encoding nucleotide sugar transporters from different species, initiated in the mid-1990s, revealed the existence of a group of related proteins with a high degree of amino acid sequence similarity [76][1]. The degree of this similarity does not seem to correlate with the substrate specificity of the transporters, as the amino acid sequences of nucleotide sugar transporters (NSTs) with the same specificity coming from different species are less like each other than the amino acid sequences of NSTs with different specificities derived from the same species.
Nucleotide sugar transporters are relatively small proteins, composed of 320–400 amino acid residues. Hydrophobicity profiles of the amino acid sequences of NSTs allow to classify them as type III membrane proteins with 6–10 TMDs. Detailed topology was first experimentally determined for the mouse CMP-Sia transporter (CST) [77][2]. In this study, CST was shown to contain 10 TMDs with N- and C-termini facing the cytoplasm.
A major breakthrough in the studies on the NST structure was made by the crystallization of the selected NSTs. In 2019, a 3-D structure of the yeast GDP-Man transporter (Vrg4), was obtained [78][3]. In the same year, the mouse CMP-Sia transporter was crystallized [79][4]. The results of these studies revealed the arrangement of TMDs, allowed for the characterization of substrate binding sites and, in the case of Vrg4, revealed the requirement for short-chain lipids in the membrane environment. Vrg4 was more active in the short- than in the long-chain lipid environment (short-chain lipids were hypothesized to enable conformational changes of Vrg4 required for the transport to occur).

2. Subcellular Localization of NSTs

All the NSTs identified to date are located either in the Golgi apparatus or in the endoplasmic reticulum. So far, the only NST displaying a dual localization is one of the SLC35A2 splicing variants, UGT2 [80][5]. The intracellular distribution of at least some of these proteins is determined by the presence of certain specific sequence motifs. The localization of UGT2 in the ER is determined by the C-terminal motif KVKGS [80][5]. The presence of similar sequences (e.g., KKTSH in SLC35B1, KDSKKN in SLC35B4, KGKGAV in SLC35D1) causes the membrane proteins to be retained in the ER [81][6].
The murine CMP-Sia transporter is located in the Golgi apparatus due to the presence of the C-terminal IIGV motif, as deletion of this sequence resulted in the retention of the NST in the ER membrane [82][7]. The C-terminal valine residue was shown to serve as an export signal from the ER [83][8]. In the case of the yeast GDP-Man, transporter amino acids 16–44 present in the N-terminal domain were shown to be a determinant of the correct subcellular localization [84][9].
Some data suggest that the intracellular distribution of NSTs is affected by their interactions with other membrane proteins. The subcellular localization of the Golgi-resident variant of the UDP-Gal transporter (UGT1) changed upon the association with the galactosylceramide synthase (UGT8) [82][7]. When over-expressed separately, UGT1 localized to the Golgi complex [80,85][5][10] whereas UGT8 was found in the ER [8][11]. Upon the simultaneous over-expression of UGT1 and UGT8, the former was shown to localize to the ER [86][12].

3. Substrate Specificity of NSTs

For many years NSTs were considered monospecific [87][13]. According to this assumption, each transporter would be responsible for the specific transfer of only one type of NS into the ER/Golgi lumen. Specificity towards more than one NS was demonstrated for some NSTs identified in lower organisms such as Leishmania sp. [88][14]. One of NSTs from Leishmania, LPG2, was shown to transport GDP-Man, GDP-Ara and GDP-Fuc [55][15].
Studies performed on C. elegans provided more examples of multi-specific NSTs. In the genome of C. elegans, 18 sequences coding for potential NSTs were identified, while the glycoconjugates produced by this nematode consist of only seven types of monosaccharides [67][16]. The SQV-7 transporter from C. elegans showed specificity for UDP-Gal, UDP-GlcA and UDP-GalNAc [64][17]. The srf-3 gene encodes a nematode membrane transporter specific for UDP-GlcNAc and UDP-Gal [65][18]. The protein encoded by the C. elegans CO3H5.2 gene was shown to be specific for UDP-GlcNAc and UDP-GalNAc [66][19]. The ZK896.9 transporter showed specificity for UDP-Glc, UDP-GlcNAc, UDP-GalNAc and UDP-Gal [67][16].
Multi-specific transporters were also identified in humans. An example is the UGTrel7/SLC35D1 protein specific for UDP-GlcNAc, UDP-GalNAc and UDP-GlcA [60,89][20][21]. Segawa et al. showed that the human UDP-Gal transporter as well as its homologue from D. melanogaster can also translocate UDP-GalNAc [39][22]. The Frc transporter identified in the fruit fly was shown to be specific for UDP-GlcA, UDP-GlcNAc, UDP-Xyl [90][23], UDP-Gal, UDP-GalNAc and UDP-Glc [91][24]. More recently, three different UDP-sugars (UDP-GlcA, UDP-GlcNAc and UDP-GalNAc) were shown to be transported into the Golgi lumen by the SLC35A5 protein [92][25].
Multi-specific NSTs were first thought to carry monosaccharides activated by only one type of diphosphonucleotide (i.e., either UDP-sugars or GDP-sugars). However, an NST specific for UDP-Xyl, UDP-GlcNAc and GDP-Fuc was identified in the fruit fly [93][26]. This is the first and, so far, only report on an NST translocating both UDP- and GDP-sugars.
Initial reports suggested that the transport of individual NSs by multi-specific transporters is a competitive process [64][17]. According to this view, different NSs would be transferred via the same active site. The C. elegans NST encoded by the CO3H5.2 gene is specific for UDP-GlcNAc and UDP-GalNAc [66][19]. Kinetic studies on a protein over-expressed in S. cerevisiae have shown, however, that both NSs are transferred to the Golgi lumen independently. The deletion mutant of this NST, lacking 16 amino acid residues located within the loop between the second and third TMDs, lost the ability to transport UDP-GalNAc but retained the ability to carry UDP-GlcNAc. The authors concluded that different portions of this NST were involved in transfer of distinct NSs. A similar phenomenon of independent transport of two different NSs was observed for the UDP-GlcNAc/UDP-Gal-specific SRF-3 protein from C. elegans [94][27].

4. Oligomerization of NSTs

According to numerous studies, NSTs were shown to form dimers or higher oligomers. In vitro dimer formation was shown for the rat UDP-GalNAc [73][28] and GDP-Fuc [74][29] transporters and for the yeast GDP-Man transporter [78,84,95][3][9][30]. The GDP-Man transporter from L. donovani was shown to form hexamers in vitro [88][14]. Oligomeric structures were also formed in vitro by the canine UDP-Gal transporter [96][31]. Moreover, SLC35A3 [97][32], SLC35A5 [92][25] and SLC35A1 [98][33] proteins were shown to dimerize in living cells.
It is not entirely clear which polypeptide fragments participate in dimerization of NSTs. The amino acid sequences of the mammalian UDP-Gal (SLC35A2) and CMP-Sia (SLC35A1) transporters and the yeast UDP-GlcNAc transporter contain a leucine zipper motif [99][34]. This motif was shown to mediate dimerization of certain proteins, but not all NSTs that tend to dimerize contain this sequence [88,95][14][30]. Moreover, the mouse CMP-Sia transporter lacking a leucine zipper motif was shown to be fully functional [77][2]. In the case of the yeast GDP-Man transporter (Vrg4) the C-terminal TMD was shown to be indispensable for dimerization [95][30].
Environmental factors were also shown to play a role in the Vrg4 dimerization. Specifically, dimerization of Vrg4 was found to be mediated by lipids as their presence was revealed at the dimer interface [78][3]. The effect of point mutations in the SLC35A1 gene on the dimerization capacity of the CMP-Sia transporter was also examined [98][33]. This study revealed that disease-causing mutations, Q110H and E196K, tend to impair/prevent dimerization of this NST.

5. Antiport Mechanism of NS Translocation

To explain the mechanism of NS transport, a model of electroneutral antiport was proposed, during which the NS is transferred to the ER and/or Golgi lumen and the corresponding nucleotide monophosphate (NMP) is transferred to the cytoplasm [51,100,101,102][35][36][37][38]. It was proposed that the nucleotide diphosphates (NDPs) formed after the transfer of the sugar residues onto the acceptors are degraded by organellar nucleotide diphosphatases (NDPases) to NMP and inorganic phosphate [48,101,103,104][37][39][40][41]. This reaction is important not only because it generates the compounds to be antiported but also due to the fact that NDPs are inhibitors of glycosyltransferases [105][42]. The transport constant Km for the majority of NSTs is in the range of 1–10 µM. The antiport model was recently supported by the crystal structures of yeast GDP-Man [78][3], mouse CMP-Sia [79][4] and Zea mays CMP-Sia [106][43] transporters.
It was proposed that NS transport results in the accumulation of NSs in the Golgi lumen [45,48,51][35][39][44]. However, the concept of accumulation appears to be challenged by the 1:1 antiport model as the former does not explain how transport into the lumen of the Golgi vesicles can be sustained without stoichiometric production of the corresponding NMP.
Several reports suggests that exchange for the corresponding NMP is not an absolute prerequisite for NS transport to occur. Deletion of a gene encoding the yeast guanosine diphosphatase resulted in a reduction in the amount of mannosylated N-glycans [107][45]. However, a different study showed that the biosynthesis of mannosylated N-glycans in yeast lacking functional guanosine diphosphatase was not significantly inhibited [108][46].
The results of some studies suggest that the transport of selected NSs is facilitated by an exchange of the corresponding NDP [51,89][21][35] or, alternatively, another type of NS [51,53,54,89][21][35][47][48]. The data obtained by Bossuyt and Blanckaert suggest the possibility that NSs can be transported in both directions. Specifically, pre-incubation of rat microsomes with UDP-GlcNAc stimulated UDP-GlcA import [54][48]. Based on these results the presence of a conjugated system of two transporters in the ER membrane was proposed, one of which would import UDP-GlcA with simultaneous export of UDP-GlcNAc and the other would import UDP-GlcNAc with concomitant export of UMP molecule formed upon incorporation of GlcA into glycoconjugates followed by UDP breakdown [109][49]. This phenomenon would be restricted to the ER as it was not observed for the Golgi apparatus [110][50].

6. Pathologies Related with Defective NSTs

Defective function of several NSTs leads to some disorders in humans. Several mutations in the gene encoding the GDP-Fuc transporter result in a disease termed CDGIIc (congenital disorder of glycosylation type IIc) or LADII [50,111][51][52]. This disease is manifested by decreased fucosylation of many glycans, including blood group antigens and selectin ligands [112,113,114][53][54][55]. The level of α-1,6-fucosylation of N-glycans (the so-called core fucosylation) is particularly reduced in CDGIIc/LADII patients [115][56]. The affected individuals suffer from dysfunctions of the immune system and exhibit developmental delay [116][57]. Surprisingly, some of the symptoms become alleviated in response to oral administration of Fuc, which is one of the GDP-Fuc precursors [113,117,118,119][54][58][59][60]. This effect suggests either the partial activity of the mutant transporters or the existence of alternative mechanisms of GDP-Fuc transport into the Golgi apparatus.
In 2005, a mutation in the gene encoding the CMP-Sia transporter was identified and the resulting disorder was termed CDGIIf [41,120][61][62]. Nowadays, the corresponding conditions are classified as SLC35A1-CDG because the CMP-Sia transporter is encoded by the SLC35A1 gene. At the molecular level, the lack of sialyl Lewis X antigen, a selectin ligand, on the surface of the patient-derived multinucleated granulocytes was demonstrated. Subsequently, more cases of SLC35A1-CDG were characterized [121,122,123][63][64][65]. The affected individuals displayed neurological symptoms such as intellectual disability, hypotonia, ataxia and seizures as well as macrothrombocytopenia.
In 2006, a disease related with a point mutation in the SLC35A3 gene, encoding the UDP-GlcNAc transporter, was characterized in cattle [124][66]. The disease was termed CVM (Complex Vertebral Malformation) as the main symptoms included severe spine and rib anomalies. In 2017, a compound heterozygous mutation in the human SLC35A3 gene was linked to severe epileptic encephalopathy with skeletal abnormalities [125][67]. Mutations in this gene have also been linked to autism [126][68].
The human ER-resident UGTrel7/SLC35D1 transporter was shown to be specific for UDP-GlcA and UDP-GalNAc [60][20]. In mice, the knockout of the corresponding gene leads to a lethal form of skeletal dysplasia [127][69]. In the affected animals the presence of truncated chains of chondroitin sulphate in proteoglycans was observed. In humans, mutations in the SLC35D1 gene cause a severe form of skeletal development abnormality, known as Schneckenbecken dysplasia [127,128][69][70].
Mutations in the SLC35A2 gene encoding the UDP-Gal transporter have also been linked to several pathologies including SLC35A2-CDG e.g., [129,130,131,132,133,134][71][72][73][74][75][76]. The affected individuals display neurological symptoms such as epilepsy, encephalopathy and hypotonia, dysfunctions of the liver, spleen, and kidneys as well as skeletal abnormalities.
 
This entry is based on the original publication:
Maszczak-Seneczko, D.; Wiktor, M.; Skurska, E.; Wiertelak, W.; Olczak, M. Delivery of Nucleotide Sugars to the Mammalian Golgi: A Very Well (un)Explained Story. Int. J. Mol. Sci. 2022, 23, 8648. https://doi.org/10.3390/ijms23158648

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