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The Diversity of Dolichol-Linked Precursors to Asn-Linked Glycans Likely Results from Secondary Loss of Sets of Glycosyltransferases

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The Diversity of Dolichol-Linked Precursors to Asn-Linked Glycans Likely Results from Secondary Loss of Sets of Glycosyltransferases The diversity of dolichol-linked precursors to Asn-linked glycans likely results from secondary loss of sets of glycosyltransferases John Samuelson*†, Sulagna Banerjee*, Paula Magnelli*, Jike Cui*, Daniel J. Kelleher‡, Reid Gilmore‡, and Phillips W. Robbins* *Department of Molecular and Cell Biology, Boston University Goldman School of Dental Medicine, 715 Albany Street, Boston, MA 02118-2932; and ‡Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, MA 01665-0103 Contributed by Phillips W. Robbins, December 17, 2004 The vast majority of eukaryotes (fungi, plants, animals, slime mold, to N-glycans of improperly folded proteins, which are retained in and euglena) synthesize Asn-linked glycans (Alg) by means of a the ER by conserved glucose-binding lectins (calnexin͞calreticulin) lipid-linked precursor dolichol-PP-GlcNAc2Man9Glc3. Knowledge of (13). Although the Alg glycosyltransferases in the lumen of ER this pathway is important because defects in the glycosyltrans- appear to be eukaryote-specific, archaea and Campylobacter sp. ferases (Alg1–Alg12 and others not yet identified), which make glycosylate the sequon Asn and͞or contain glycosyltransferases dolichol-PP-glycans, lead to numerous congenital disorders of with domains like those of Alg1, Alg2, Alg7, and STT3 (1, 14–16). glycosylation. Here we used bioinformatic and experimental Protists, unicellular eukaryotes, suggest three notable exceptions methods to characterize Alg glycosyltransferases and dolichol- to the N-linked glycosylation path described in yeast and animals PP-glycans of diverse protists, including many human patho- (17). First, the kinetoplastid Trypanosoma cruzi (cause of Chagas gens, with the following major conclusions. First, it is demon- myocarditis), fails to glucosylate the dolichol-PP-linked precursor strated that common ancestry is a useful method of predicting and so makes dolichol-PP-GlcNAc2Man9 (18). Another kinetoplas- the Alg glycosyltransferase inventory of each eukaryote. Second, tid Leishmania mexicana (cause of skin ulcers) lacks the manno- in the vast majority of cases, this inventory accurately predicts the sylating activities of Alg9 and Alg12 and makes dolichol-PP- dolichol-PP-glycans observed. Third, Alg glycosyltransferases are GlcNAc2Man6 (Alg9 adds both the 7th and 9th Man residues) (18). missing in sets from each organism (e.g., all of the glycosyltrans- Second, Tetrahymena pyriformis, which is a free-living ciliate, lacks ferases that add glucose and mannose are absent from Giardia and all of the mannosylating activity in the ER lumen and makes Plasmodium). Fourth, dolichol-PP-GlcNAc2Man5 (present in Entam- dolichol-PP-GlcNAc2Man5Glc3 (19). Third, it has been difficult to oeba and Trichomonas) and dolichol-PP- and N-linked GlcNAc2 identify N-glycans from either Giardia lamblia (cause of diarrhea) (present in Giardia) have not been identified previously in wild- or Plasmodium falicparum (cause of severe malaria) (20–22). type organisms. Finally, the present diversity of protist and fungal Because these observations of unique protist glycans were dolichol-PP-linked glycans appears to result from secondary loss of made before identification of multiple Alg glycosyltransferases glycosyltransferases from a common ancestor that contained the and͞or whole-genome sequencing of these protists, numerous complete set of Alg glycosyltransferases. important questions remain concerning the diversity of N-glycan precursors among eukaryotes. First, are the same Alg glycosyl- evolution ͉ N-glycans ͉ protist transferases conserved across all eukaryotes, and are these Alg glycosyltransferases specific to eukaryotes or are they also he majority of eukaryotes studied to date (fungi, plants, ani- present in prokaryotes? Second, are kinetoplastids [Trypano- Tmals, slime mold, and euglena) synthesize Asn-linked glycans soma cruzi and Trypanosoma brucei (cause of African sleeping (Alg) by means of a lipid-linked precursor dolichol-PP- sickness)] missing the genes encoding the glucosylating enzymes GlcNAc2Man9Glc3 (Fig. 1A) (1–3). Each of the 14 sugars is added or are the genes present but silent, and similarly, is Tetrahymena to the lipid-linked precursor by means of a specific glycosyltrans- missing the set of genes encoding mannosylating enzymes in the ferase (Alg1–Alg12 and others as yet specified), which were num- lumen of the ER? Third, what Alg glycosyltransferases are bered according to the order of their discovery rather than by the missing from Giardia and Plasmodium? Fourth, what is the sequence of enzymatic steps (4–6). Defects in these Alg glycosyl- diversity of predicted Alg glycosyltransferases of other protists transferases lead to numerous congenital disorders of glycosylation, (e.g., Entamoeba histolytica, Trichomonas vaginalis, Toxoplasma which can cause dysmorphic features and mental retardation (7). gondii, and Cryptosporidium parvum, which cause dysentery, We and others used the budding yeast Saccharomyces cerevisiae vaginitis, birth defects, and diarrhea, respectively), and what are mutants to characterize many but not all of the Alg glycosyltrans- the Alg glycosyltransferases of Encephalitozoon cuniculi (an ferases, which are present on the cytosolic aspect of the ER. These opportunistic fungus with a dramatically reduced genome) and glycosyltransferases include Alg7, which adds phospho-GlcNAc to Cryptococcus neoformans (an opportunistic fungus that is dis- dolichol phosphate, and Alg1, Alg2, and Alg11, which add the first, tantly related to Saccharomyces)? Fifth, do the predicted Alg second, and fifth Man residues, respectively (Fig. 1A). Dolichol- glycosyltransferases correlate with the dolichol-PP-linked gly- PP-GlcNAc2Man5 is flipped into the lumen of the ER by a flippase cans of each protist or fungus? Sixth, does the pattern distribu- (Rft1) (8). Within the ER lumen, mannosyltransferases Alg3, Alg9, tion of Alg glycosyltransferases across protists, fungi, and meta- and Alg12 make dolichol-PP-GlcNAc2Man9 by using dolichol-P- zoa suggest whether these glycosyltransferases have been added Man (made by Dpm1) as the sugar donor (Fig. 1A) (1, 9). Also to or lost from eukaryotes during their evolution (23, 24)? within the ER lumen, glucosyltransferases Alg6, Alg8, and Alg10 make dolichol-PP-GlcNAc2Man9Glc3 by using dolichol-P-Glc (made by Alg5) as the sugar donor (Fig. 1A). Freely available online through the PNAS open access option. An oligosaccharyltransferase (OST), which contains a catalytic Abbreviations: Alg, Asn-linked glycan; OST; oligosaccharyltransferase; TMH, transmem- peptide, STT3, transfers the dolichol-PP-linked oligosaccharide to brane helix. ‘‘sequon’’ Asn residues (N-X-T͞S) on nascent peptides (Fig. 1A) †To whom correspondence should be addressed: E-mail: [email protected]. (10–12). A UDP-Glc:glycoprotein glucosyltransferase adds glucose © 2005 by The National Academy of Sciences of the USA 1548–1553 ͉ PNAS ͉ February 1, 2005 ͉ vol. 102 ͉ no. 5 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0409460102 Downloaded by guest on September 26, 2021 Fig. 1. The inventory of Alg glycosyltransferases and predicted dolichol-linked glycans vary dramatically among protists and fungi. Predicted Alg glycosyl- transferases and dolichol-linked glycans of Saccharomyces cerevisiae, Homo sapiens, and Dictyostelium discoideum (A), Trypanosoma cruzi, Trypanosoma brucei, Leishmania major, and Cryptococcus neoformans (B), Tetrahymena thermophilia, Toxoplasma gondii, and Cryptosporidium parvum (C), Entamoeba histolytica and Trichomonas vaginalis (D), Plasmodium falciparum and Giardia lamblia (E), and Encephalitozoon cuniculi (F) (see also Table 1). With the exceptions of Saccharomyces and Homo, sets of Alg glycosyltransferases were identified here. Names of organisms, whose dolichol-PP-linked glycans were previously identified (e.g., Saccharomyces), are indicated in black. Names of organisms, whose dolichol-PP-linked glycans were identified here (e.g., Cryptococcus), are indicated in red. Names of organisms, whose dolichol-PP-linked glycans have not yet been identified (e.g., Cryptosporidium), are indicated in green. EVOLUTION 14 Materials and Methods mutant incubated with C-Man, GlcNAc2Man9 from a Saccha- ⌬ Use of Bioinformatics to Identify Alg Glycosyltransferases from Di- romyces alg6 mutant, and unlabeled GlcNAc and GlcNAc2. verse Protists and Fungi. Twelve Saccharomyces Alg glycosyltrans- For identification of N-glycans, Entamoeba, Trichomonas, and ferases, DPM1, and STT3 were used to search predicted proteins Giardia were labeled with mannose and GlcN for2hinmedium of eukaryotes, which have been sequenced in their entirety or containing 0.1% glucose before washing and lyophilization. The ͞ ͞ near entirety (Plasmodium falciparum, Encephalitozoon cuniculi, dry-cell pellet was delipidated with chloroform methanol water, Cryptosporidium parvum, Giardia lamblia, Homo sapiens, and glycosylphosphatidylinositol precursors were removed with water- Arabidopsis thaliana)intheNR protein database of the National saturated butanol, and glycogen and other free glycans were removed with 50% methanol (35). The clean pellet was finely Center for Biotechnology Information by using PSI-BLAST (25– resuspended by using a manual homogenizer in 500 ␮l Tris⅐HCl 30). BLASTP or TBLASTN searches of Entamoeba histolytica, Trichomonas vaginalis, Trypanosoma brucei, Trypanosoma cruzi, (0.1M, pH 8) and incubated with 50 milliunits of peptide-N- and Tetrhymena thermophilia were performed at web sites man- glycosidase F (PNGaseF)
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