Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Milani, Donatella; Cagnoli, Giulia; Baccarin, Marco; Alfei, Enrico; Guerneri, Silvana; Esposito, Susanna

doi:10.1111/cga.12164

Cited by 8 publications

(13 citation statements)

References 14 publications

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“…Based on our biochemical data and the available structural information for homomeric cisPTs, MaUPPS-B have similar impact on MaUPPS activity as those in distantly related hcisPT, we postulate a common mechanism for both enzymes. 16 In summary, this study strongly advances the concept that eukaryotic cisPT is composed of two subunits, NgBR and hCIT, and this two component system is conserved in…”

Section: Discussionsupporting

confidence: 54%

“…Our group discovered that unlike UPPS, mammalian and fungal cisPT is heteromeric complex consisting of NgBR (Nus1) and hCIT (DHDDS) subunits in human cells and these findings were confirmed for a number of plant cisPTs (6-10) demonstrating a major difference in the composition of cisPT activity in prokaryotes and eukaryotes. Moreover, loss of function mutations identified in patients via exome sequencing in either NgBR or hCIT causes a congenital glycosylation disorder, and results in severe clinical manifestations including cognitive defects and retinitis pigmentosa (11)(12)(13)(14)(15) and microdeletions within NgBR locus are linked to pediatric epilepsy (16,17). Further phylogenetic analysis of NgBR and UPPS suggests 4 that a C-terminal motif important for mammalian and fungal cisPT is shared by the single subunit cisPT UPPS (1).…”

Section: Introductionmentioning

confidence: 99%

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Purification of the mammalian NgBR/hCITcis-prenyltransferase complex: Identification of a conserved carboxyterminal RxG motif crucial for enzymatic activity

Grabińska¹,

Edani²,

Park³

et al. 2017

Preprint

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2 Summarycis-Prenyltransferases (cisPTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. In eukaryotes and archaea, cisPT is the first enzyme committed to the synthesis of dolichyl-phosphate (DolP). DolP is obligate lipid carrier in protein glycosylation reactions in mammals. The homodimeric bacterial enzyme, undecaprenyl diphosphate synthase (UPPS) generates 11 isoprene units and has been structurally and mechanistically characterized in great detail. Recently our group discovered that unlike UPPS, mammalian cisPT is a heteromer consisting of NgBR (NUS1) and hCIT (DHDDS) subunits and this composition has been confirmed in plants and fungal cisPTs. Here, we establish the first purification system for heteromeric cisPT and show that both NgBR and hCIT subunits function in catalysis and substrate binding. Finally, we identified a critical RxG sequence in the Cterminal tail of NgBR that is conserved and essential for enzyme activity across phyla.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Purification of the mammalian NgBR/hCITcis-prenyltransferase complex: Identification of a conserved carboxyterminal RxG motif crucial for enzymatic activity

Grabińska¹,

Edani²,

Park³

et al. 2017

Preprint

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show abstract

“…In both instances, mutations in NgBR or hCIT show altered ratios of dolichol chain lengths when measured in urine and plasma from affected carriers (47,80). Finally, chromosomal deletion within NgBR locus may play a role in driving susceptibility to pediatric epilepsy and congenital anomalies (81,82). Because epilepsy is commonly observed in congenital disorders of glycosylation (83), observed symptoms may be consistent with defects in dolichol synthesis and hypoglycosylation.…”

Section: Genetic Validation Of Two-component Ngbr/hcit Complex In Humansmentioning

confidence: 99%

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

Grabińska

Park

Sessa

2016

Journal of Biological Chemistry

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cis-Prenyltransferases (cis-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. cis-PTs catalyze consecutive condensation reactions of allylic diphosphate acceptor with isopentenyl diphosphate (IPP) in the cis (Z) configuration to generate linear polyprenyl diphosphate. The chain lengths of isoprenoid carbon skeletons vary widely from neryl pyrophosphate (C 10 ) to natural rubber (C >10,000 ). The homo-dimeric bacterial enzyme, undecaprenyl diphosphate synthase (UPPS), has been structurally and mechanistically characterized in great detail and serves as a model for understanding the mode of action of eukaryotic cis-PTs. However, recent experiments have revealed that mammals, fungal, and long-chain plant cis-PTs are heteromeric enzymes composed of two distantly related subunits. In this review, the classification, function, and evolution of cis-PTs will be discussed with a special emphasis on the role of the newly described NgBR/Nus1 subunit and its plants' orthologs as essential, structural components of the cis-PTs activity.

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“…Our group discovered that unlike UPPS, mammalian and fungal cis-PT is heteromeric complex consisting of NgBR (Nus1) and hCIT (dehydrodolichol diphosphate synthase) subunits in human cells (6,7), and these findings were confirmed for a number of plant cis-PTs (8 -12), demonstrating a major difference in the composition of cis-PT activity in prokaryotes and eukaryotes. Moreover, loss of function mutations identified in patients via exome sequencing in either NgBR or hCIT causes a congenital glycosylation disorder and results in severe clinical manifestations including cognitive defects and retinitis pigmentosa (6,(13)(14)(15)(16), and microdeletions within NgBR locus are linked to pediatric epilepsy (17,18). Further phylogenetic analysis of NgBR and UPPS suggests that a C-terminal motif important for mammalian and fungal cis-PT is shared by the single-subunit cis-PT UPPS (1).…”

mentioning

confidence: 99%

A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity

Grabińska

Edani

Park

et al. 2017

Journal of Biological Chemistry

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-Prenyltransferases (-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. In eukaryotes and archaea, -PT is the first enzyme committed to the synthesis of dolichyl phosphate, an obligate lipid carrier in protein glycosylation reactions. The homodimeric bacterial enzyme, undecaprenyl diphosphate synthase, generates 11 isoprene units and has been structurally and mechanistically characterized in great detail. Recently, we discovered that unlike undecaprenyl diphosphate synthase, mammalian-PT is a heteromer consisting of NgBR (Nus1) and hCIT (dehydrodolichol diphosphate synthase) subunits, and this composition has been confirmed in plants and fungal -PTs. Here, we establish the first purification system for heteromeric-PT and show that both NgBR and hCIT subunits function in catalysis and substrate binding. Finally, we identified a critical RG sequence in the C-terminal tail of NgBR that is conserved and essential for enzyme activity across phyla. In summary, our findings show that eukaryotic -PT is composed of the NgBR and hCIT subunits. The strong conservation of the RG motif among NgBR orthologs indicates that this subunit is critical for the synthesis of polyprenol diphosphates and cellular function.

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Insights into 6q21‐q22: Refinement of the critical region for acro‐cardio‐facial syndrome

Cited by 8 publications

References 14 publications

Purification of the mammalian NgBR/hCITcis-prenyltransferase complex: Identification of a conserved carboxyterminal RxG motif crucial for enzymatic activity

Purification of the mammalian NgBR/hCITcis-prenyltransferase complex: Identification of a conserved carboxyterminal RxG motif crucial for enzymatic activity

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases

A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity

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