Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex

Bar-El, Michal Lisnyansky; Vaňková, Pavla; Yeheskel, Adva; Simhaev, Luba; Engel, Hamutal; Man, Petr; Haitin, Yoni; Giladi, Moshe

doi:10.1038/s41467-020-18970-z

Cited by 27 publications

(61 citation statements)

References 47 publications

(98 reference statements)

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“…These atypical TS enzymes include DHDPPS and its evolutionarily related obligate partner NUS1, also known as NOGOB receptor (NOGOBR) [( 22), see also (23)(24)(25)]; indeed, there are potential primary structure similarities between NUS1 and NR LBDs (Figure 3B and Figure S8). Of note, this subgroup is also built around a seven-helix core (26), and the regions of similarity overlap accurately with the conserved seven-helix core identified in NRs (compare Figures S6 and S8); NR LBDs may therefore be evolutionarily related to this specific TS subfamily.…”

Section: Nrs Are Most Similar To the Ts Dehydrodolichyl Pyrophosphate Synthasementioning

confidence: 61%

Evidence that nuclear receptors evolved from terpene synthases

Houston

Hanna

Lathe

et al. 2021

Preprint

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Ligand-activated nuclear receptors (NRs) including steroid receptors orchestrate development, growth, and reproduction across all animal lifeforms - the Metazoa - but how NRs evolved remains mysterious. Given the universality of terpenoids - including steroids and retinoids - as activating NR ligands, we asked if NRs might have evolved from enzymes that catalyze terpene synthesis and metabolism. We provide evidence suggesting that NRs are a sub-branch of the terpene synthase (TS) enzyme superfamily. Based on over ten thousand 3D structural comparisons, backed up by multiple primary sequence alignments and mapping of ligand-contacting residues, we report that the NR ligand-binding domain and TS enzymes share a conserved core of seven α-helical segments. Primary sequence comparisons reveal potential amino acid sequence similarities between NRs and the subfamily of cis-isoprene transferases, in particular dehydrodolichyl pyrophosphate synthase (DHDPPS) and its obligate partner, NUS1/NOGOB receptor. Our results suggest that a ligand-gated receptor may have arisen from an enzyme antecedent, and thus resolve the long-standing debate about whether the ancestral NR was unliganded. This would also explain aspects of NR ligand 'promiscuity', with implications for the development of pharmaceuticals targeting NRs and TS enzymes.

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Section: Nrs Are Most Similar To the Ts Dehydrodolichyl Pyrophosphate Synthasementioning

confidence: 61%

Evidence that nuclear receptors evolved from terpene synthases

Houston

Hanna

Lathe

et al. 2021

Preprint

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“…The human cis-prenyltransferase is an enzymatic complex essential for protein N-glycosylation. It is composed of two structurally and functionally distinct subunit types ( Grabińska et al, 2016 ; Bar-El et al, 2020 ; Edani et al, 2020 ). These include the catalytically active DHDDS and the quiescent Nogo-B receptor (NgBR) subunits ( Harrison et al, 2011 ; Bar-El et al, 2020 ; Edani et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…It is composed of two structurally and functionally distinct subunit types ( Grabińska et al, 2016 ; Bar-El et al, 2020 ; Edani et al, 2020 ). These include the catalytically active DHDDS and the quiescent Nogo-B receptor (NgBR) subunits ( Harrison et al, 2011 ; Bar-El et al, 2020 ; Edani et al, 2020 ). Importantly, the distal C-terminus of NgBR transverses across the interface with DHDDS, directly participating in active-site formation and functional coupling between the two subunits ( Bar-El et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…These include the catalytically active DHDDS and the quiescent Nogo-B receptor (NgBR) subunits ( Harrison et al, 2011 ; Bar-El et al, 2020 ; Edani et al, 2020 ). Importantly, the distal C-terminus of NgBR transverses across the interface with DHDDS, directly participating in active-site formation and functional coupling between the two subunits ( Bar-El et al, 2020 ). The heterodimerization architecture supports the notion that although DHDDS is considered as the catalytically active subunit, both subunits are necessary for efficient dolichol synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, these mutations can be subdivided into mutations that directly or indirectly interfere with substrate association. These mutations result in a similar reduction in catalytic activity and are clinically associated with developmental epileptic encephalopathies ( Hamdan et al, 2017 ; Bar-El et al, 2020 ). The functional consequences of disease mutations clustered around the active-site, and in combination with molecular dynamics simulations, suggested a mechanism for the human cis-prenyltransferase dysfunction in RP ( Bar-El et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of Dehydrodolichyl Diphosphate Synthase in the Drosophila Retina Leads to a Unique Pattern of Retinal Degeneration

Brandwine

Ifrah

Bialistoky

et al. 2021

Front. Mol. Neurosci.

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Dehydrodolichyl diphosphate synthase (DHDDS) is a ubiquitously expressed enzyme that catalyzes cis-prenyl chain elongation to produce the poly-prenyl backbone of dolichol. It appears in all tissues including the nervous system and it is a highly conserved enzyme that can be found in all animal species. Individuals who have biallelic missense mutations in the DHDDS gene are presented with non-syndromic retinitis pigmentosa with unknown underlying mechanism. We have used the Drosophila model to compromise DHDDS ortholog gene (CG10778) in order to look for cellular and molecular mechanisms that, when defective, might be responsible for this retinal disease. The Gal4/UAS system was used to suppress the expression of CG10778 via RNAi-mediated-knockdown in various tissues. The resulting phenotypes were assessed using q-RT-PCR, transmission-electron-microscopy (TEM), electroretinogram, antibody staining and Western blot analysis. Targeted knockdown of CG10778-mRNA in the early embryo using the actin promoter or in the developing wings using the nub promoter resulted in lethality, or wings loss, respectively. Targeted expression of CG10778-RNAi using the glass multiple reporter (GMR)-Gal4 driver (GMR-DHDDS-RNAi) in the larva eye disc and pupal retina resulted in a complex phenotype: (a) TEM retinal sections revealed a unique pattern of retinal-degeneration, where photoreceptors R2 and R5 exhibited a nearly normal structure of their signaling-compartment (rhabdomere), but only at the region of the nucleus, while all other photoreceptors showed retinal degeneration at all regions. (b) Western blot analysis revealed a drastic reduction in rhodopsin levels in GMR-DHDDS-RNAi-flies and TEM sections showed an abnormal accumulation of endoplasmic reticulum (ER). To conclude, compromising DHDDS in the developing retina, while allowing formation of the retina, resulted in a unique pattern of retinal degeneration, characterized by a dramatic reduction in rhodopsin protein level and an abnormal accumulation of ER membranes in the photoreceptors cells, thus indicating that DHDDS is essential for normal retinal formation.

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Adult‐onset rapidly worsening progressive myoclonic epilepsy caused by a novel variant in DHDDS

Kim

Son

et al. 2021

Ann Clin Transl Neurol

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Progressive myoclonic epilepsy (PME) is a heterogeneous neurogenetic disorder manifesting as progressive myoclonus, seizure, and ataxia. We report a case of PME caused by a novel DHDDS variant. Additionally, by reviewing the literature on DHDDS mutations, we compared the phenotype of our patient with previously reported phenotypes. We identified DHDDS (c.638G>A, p. Ser213-Asn) as a likely pathogenic variant. The literature review revealed 15 PME patients with DHDDS mutations from 13 unrelated families. According to previous studies, late-onset patients tend to have a slow-progressive disease course. Although his myoclonus and ataxia were adult onset, our patient experienced rapid disease aggravation.

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Structural basis of heterotetrameric assembly and disease mutations in the human cis-prenyltransferase complex

Cited by 27 publications

References 47 publications

Evidence that nuclear receptors evolved from terpene synthases

Evidence that nuclear receptors evolved from terpene synthases

Knockdown of Dehydrodolichyl Diphosphate Synthase in the Drosophila Retina Leads to a Unique Pattern of Retinal Degeneration

Adult‐onset rapidly worsening progressive myoclonic epilepsy caused by a novel variant in DHDDS

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