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

Grabińska, Kariona A.; Park, Eon Joo; Sessa, William C.

doi:10.1074/jbc.r116.739490

Cited by 71 publications

(94 citation statements)

References 89 publications

(95 reference statements)

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“…Bacterial CPTs synthesize the Pren-11 (C55) polyprenol known as undecaprenyl diphosphate, which as mentioned above, functions in peptidoglycan biosynthesis, while animal CPTs are involved in the synthesis of longer chain dolichols that serve an indispensable role in protein N-glycosylation. Bacterial and animal CPTs are phylogenetically distinct from one another, and while CPTs from microbes operate autonomously, their animal counterparts strictly require a distantly related partner protein for stability and enzymatic activity (Harrison et al, 2011;Park et al, 2014;Grabińska et al, 2016). Given that plants accumulate both classes of polyisoprenoids, it is not surprising that their CPT families can be phylogenetically divided into two groups: those predicted to act alone and synthesize polyprenols and those requiring a partner protein for dolichol biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

Polyprenols Are Synthesized by a Plastidial cis-Prenyltransferase and Influence Photosynthetic Performance

et al. 2017

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Plants accumulate a family of hydrophobic polymers known as polyprenols, yet how they are synthesized, where they reside in the cell, and what role they serve is largely unknown. Using Arabidopsis thaliana as a model, we present evidence for the involvement of a plastidial cis-prenyltransferase (AtCPT7) in polyprenol synthesis. Gene inactivation and RNAi-mediated knockdown of AtCPT7 eliminated leaf polyprenols, while its overexpression increased their content. Complementation tests in the polyprenol-deficient yeast Δrer2 mutant and enzyme assays with recombinant AtCPT7 confirmed that the enzyme synthesizes polyprenols of ;55 carbons in length using geranylgeranyl diphosphate (GGPP) and isopentenyl diphosphate as substrates. Immunodetection and in vivo localization of AtCPT7 fluorescent protein fusions showed that AtCPT7 resides in the stroma of mesophyll chloroplasts. The enzymatic products of AtCPT7 accumulate in thylakoid membranes, and in their absence, thylakoids adopt an increasingly "fluid membrane" state. Chlorophyll fluorescence measurements from the leaves of polyprenol-deficient plants revealed impaired photosystem II operating efficiency, and their thylakoids exhibited a decreased rate of electron transport. These results establish that (1) plastidial AtCPT7 extends the length of GGPP to ;55 carbons, which then accumulate in thylakoid membranes; and (2) these polyprenols influence photosynthetic performance through their modulation of thylakoid membrane dynamics.

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Section: Introductionmentioning

confidence: 99%

Polyprenols Are Synthesized by a Plastidial cis-Prenyltransferase and Influence Photosynthetic Performance

et al. 2017

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“…cis-prenyltransferases form homodimers via a conserved dimerization interface throughout the phylogenetic tree [7,14]. The structure of these homodimers was extensively studied at high-resolution [22].…”

Section: Human Dhdds Forms a Monodisperse Homodimer -Short-and Mediummentioning

confidence: 99%

“…Dehydrodolichyl diphosphate synthase (DHDDS) together with Nogo-B receptor (NgBR) form the human cis-prenyltransferase complex [6,7]. This complex catalyzes the formation of dehydrodolichyl diphosphate (DHDD), a long-chain polyprenyl serving as a precursor for Dol-P. DHDD is synthesized by chain elongation of farnesyl diphosphate (FPP) via multiple condensations with isopentenyl diphosphate (IPP) ( Figure 1A) [6].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, this modification is crucial for proper protein folding, oligomerization, quality control, sorting, and transport [2]. Accordingly, even slight variations in protein glycosylation can markedly affect proteins structure and function [3] and thus, glycosylation disorders result in a wide range of clinical syndromes affecting practically every organ system [4,5].Dehydrodolichyl diphosphate synthase (DHDDS) together with Nogo-B receptor (NgBR) form the human cis-prenyltransferase complex [6,7]. This complex catalyzes the formation of dehydrodolichyl diphosphate (DHDD), a long-chain polyprenyl serving as a precursor for Dol-P. DHDD is synthesized by chain elongation of farnesyl diphosphate (FPP) via multiple condensations with isopentenyl diphosphate (IPP) ( Figure 1A) [6].…”

mentioning

confidence: 99%

“…This complex catalyzes the formation of dehydrodolichyl diphosphate (DHDD), a long-chain polyprenyl serving as a precursor for Dol-P. DHDD is synthesized by chain elongation of farnesyl diphosphate (FPP) via multiple condensations with isopentenyl diphosphate (IPP) ( Figure 1A) [6]. Importantly, while previous studies revealed that DHDDS is required and sufficient for this catalytic activity, NgBR induces an increase in the expression and activity of the complex but exhibits no catalytic activity [6][7][8]. In line with the important role of DHDDS in protein glycosylation, mutations in DHDDS were recently shown to cause autosomal recessive retinitis pigmentosa [9,10], a fatal glycosylation disorder [11], and developmental epileptic encephalopathies [12].Despite the clinical importance of DHDDS, it was not structurally and functionally characterized to date.…”

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confidence: 99%

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Integrative modelling of the full-length human dehydrodolichyl diphosphate synthase using a hybrid computational and experimental approach

Barel

Lee

et al. 2019

Preprint

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Dehydrodolichyl diphosphate synthase (DHDDS) and Nogo-B receptor (NgBR) form the heteromeric human cis-prenyltransferase complex, synthesizing the precursor for the glycosyl carrier involved in N-linked protein glycosylation. In line with the important role of N-glycosylation in protein biogenesis, mutations in DHDDS, the catalytic subunit of the complex, were shown to result in human diseases. Importantly, well-characterized DHDDS homologs function as homodimers and not as heteromeric complexes. Moreover, DHDDS encompasses a C-terminal region, which does not converge with any known conserved domains. Therefore, despite the clinical importance of DHDDS, our understating of its structure-function relations remains poor. Here, we provide a structural model for the full-length human DHDDS using a multidisciplinary experimental and computational approach. Our model suggests that the C-terminal domain of DHDDS forms a helix-loop-helix motif, tightly packed against the core catalytic cis-prenyltransferase domain. This model is consistent with small-angle X-ray scattering data, indicating that the full-length DHDDS maintains a similar conformation in solution. Moreover, hydrogen-deuterium exchange mass-spectrometry experiments show time-dependent deuterium uptake in the C-terminal domain, consistent with its overall folded state. Finally, we provide a model for the DHDDS-NgBR heterodimer, offering a structural framework for future structural and functional studies of the human cis-prenyltransferase complex.Keywords: cis-prenyltransferase, computational modelling, hydrogen-deuterium exchange mass-spectrometry, small-angle X-ray scattering, enzyme kinetics, DHDDS IntroductionProtein N-glycosylation is a critical post-translational modification, in which an oligosaccharide moiety is transferred from the glycosyl carrier dolichol-phosphate (Dol-P) and covalently attaches to a polypeptide chain via an asparagine residue [1]. Following protein conjugation, the oligosaccharide is further modified, increasing the functional and structural diversity of the proteome [2]. Indeed, this modification is crucial for proper protein folding, oligomerization, quality control, sorting, and transport [2]. Accordingly, even slight variations in protein glycosylation can markedly affect proteins structure and function [3] and thus, glycosylation disorders result in a wide range of clinical syndromes affecting practically every organ system [4,5].Dehydrodolichyl diphosphate synthase (DHDDS) together with Nogo-B receptor (NgBR) form the human cis-prenyltransferase complex [6,7]. This complex catalyzes the formation of dehydrodolichyl diphosphate (DHDD), a long-chain polyprenyl serving as a precursor for Dol-P. DHDD is synthesized by chain elongation of farnesyl diphosphate (FPP) via multiple condensations with isopentenyl diphosphate (IPP) ( Figure 1A) [6]. Importantly, while previous studies revealed that DHDDS is required and sufficient for this catalytic activity, NgBR induces an increase in the expression and activity of the complex but ex...

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Structure, catalysis, and inhibition mechanism of prenyltransferase

Chang¹,

Cheng²,

Wang

2020

IUBMB Life

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Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer dimethylallyl diphosphate as the building blocks. Isoprenoids are structurally and functionally diverse and include dolichols, steroid hormones, carotenoids, retinoids, aromatic metabolites, the isoprenoid side-chain of ubiquinone, and isoprenoid attached signaling proteins. Productions of isoprenoids are catalyzed by a group of enzymes known as prenyltransferases, such as farnesyltransferases, geranylgeranyltransferases, terpenoid cyclase, squalene synthase, aromatic prenyltransferase, and cis-and trans-prenyltransferases. Because these enzymes are key in cellular processes and metabolic pathways, they are expected to be potential targets in new drug discovery. In this review, six distinct subsets of characterized prenyltransferases are structurally and mechanistically classified, including (1) head-to-tail prenyl synthase, (2) head-to-head prenyl synthase, (3) head-tomiddle prenyl synthase, (4) terpenoid cyclase, (5) aromatic prenyltransferase, and (6) protein prenylation. Inhibitors of those enzymes for potential therapies against several diseases are discussed. Lastly, recent results on the structures of integral membrane enzyme, undecaprenyl pyrophosphate phosphatase, are also discussed.

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

Cited by 71 publications

References 89 publications

Polyprenols Are Synthesized by a Plastidial cis-Prenyltransferase and Influence Photosynthetic Performance

Polyprenols Are Synthesized by a Plastidial cis-Prenyltransferase and Influence Photosynthetic Performance

Integrative modelling of the full-length human dehydrodolichyl diphosphate synthase using a hybrid computational and experimental approach

Structure, catalysis, and inhibition mechanism of prenyltransferase

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