Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells

Brylski, Oliver; Shrestha, Puja; House, Philip J.; Gnutt, Patricia; Mueller, Jonathan Wolf; Ebbinghaus, Simon

doi:10.3389/fmolb.2022.860387

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…Despite this high temperature, (CAG) 20 RNA unfolding showed no indication of self-association due to intermolecular FRET (Figure S7B), which would be expected in this case due to the high ratio of labeled to endogenous CAG-RNA. In fact, FReI is very sensitive to such self-association events upon unfolding. ,,, Measurements of (CAG) 20 RNA in concentrated adenosine triphosphate (ATP) solutions (15 and 20 mM) led to microscopically visible aggregates, showing that self-association could be indeed detected for the (CAG) 20 RNA construct (Figure S8). Thus, the data suggest that CAG-RNA entanglements do not form in speckles (or the nucleoplasm), even at high temperatures and at concentrations much higher than those of endogenous CAG-RNA levels.…”

Section: Resultsmentioning

confidence: 99%

CAG-Repeat RNA Hairpin Folding and Recruitment to Nuclear Speckles with a Pivotal Role of ATP as a Cosolute

et al. 2023

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A hallmark of Huntington's disease (HD) is a prolonged polyglutamine sequence in the huntingtin protein and, correspondingly, an expanded cytosine, adenine, and guanine (CAG) triplet repeat region in the mRNA. A majority of studies investigating disease pathology were concerned with toxic huntingtin protein, but the mRNA moved into focus due to its recruitment to RNA foci and emerging novel therapeutic approaches targeting the mRNA. A hallmark of CAG-RNA is that it forms a stable hairpin in vitro which seems to be crucial for specific protein interactions. Using in-cell folding experiments, we show that the CAG-RNA is largely destabilized in cells compared to dilute buffer solutions but remains folded in the cytoplasm and nucleus. Surprisingly, we found the same folding stability in the nucleoplasm and in nuclear speckles under physiological conditions suggesting that CAG-RNA does not undergo a conformational transition upon recruitment to the nuclear speckles. We found that the metabolite adenosine triphosphate (ATP) plays a crucial role in promoting unfolding, enabling its recruitment to nuclear speckles and preserving its mobility. Using in vitro experiments and molecular dynamics simulations, we found that the ATP effects can be attributed to a direct interaction of ATP with the nucleobases of the CAG-RNA rather than ATP acting as "a fuel" for helicase activity. ATP-driven changes in CAG-RNA homeostasis could be disease-relevant since mitochondrial function is affected in HD disease progression leading to a decline in cellular ATP levels.

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Section: Resultsmentioning

confidence: 99%

CAG-Repeat RNA Hairpin Folding and Recruitment to Nuclear Speckles with a Pivotal Role of ATP as a Cosolute

et al. 2023

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“…PAPSS2 encodes human PAPS synthase 2, a highly conserved enzyme involved in sulfur metabolism and in sulfation of proteins, glycans, and steroid hormones [25]. In humans, PAPSS2 pathogenic variants originate several disorders including skeletal dysplasia, androgen excess, and polycystic ovary syndrome [26]. At this moment, no obvious role of this gene in DR is apparent and additional studies will be needed to replicate this association.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genetic Variants for Diabetic Retinopathy Risk Applying Exome Sequencing in Extreme Phenotypes

Zenteno,

Chacón-Camacho,

Ordoñez-Labastida

et al. 2024

BioMed Research International

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Background. Diabetic retinopathy (DR) risk has been shown to vary depending on ethnic backgrounds, and thus, it is worthy that underrepresented populations are analyzed for the potential identification of DR-associated genetic variants. We conducted a case-control study for the identification of DR-risk variants in Mexican population. Methods. We ascertained 60 type 2 diabetes mellitus (T2DM) patients. Cases (n=30) were patients with advanced proliferative DR (PDR) with less than 15 years after a T2DM diagnosis while controls (n=30) were patients with no DR 15 years after the diagnosis of T2DM. Exome sequencing was performed in all patients, and the frequency of rare variants was compared. In addition, the frequency of variants occurring in a set of 169 DR-associated genes were compared. Results. Statistically significant differences were identified for rare missense and splice variants and for rare splice variants occurring more than once in either group. A strong statistical difference was observed when the number of rare missense variants with an aggregated prediction of pathogenicity and occurring more than once in either group was compared (p=0.0035). Moreover, 8 variants identified more than once in either group, occurring in previously identified DR-associated genes were recognized. The p.Pro234Ser KIR2DS4 variant showed a strong protective effect (OR=0.04 [0.001–0.36]; p=0.04). Conclusions. Our study showed an enrichment of rare splice acceptor/donor variants in patients with PDR and identified a potential protective variant in KIR2DS4. Although statistical significance was not reached, our results support the replication of 8 previously identified DR-associated genes.

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“…PAPSS2 plays significant roles in androgen excess, bone dysplasia, and spondyloepimetaphyseal dysplasia when disrupted ( 34 ). PAPSS1 cannot replace PAPSS2 in terms of function, yet only limited information is available in the literature on this kinase type ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Adenylyl-Sulfate Kinase (Met14)-Dependent Cysteine and Methionine Biosynthesis Pathways Contribute Distinctively to Pathobiological Processes in Cryptococcus neoformans

et al. 2023

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Disease-Related Protein Variants of the Highly Conserved Enzyme PAPSS2 Show Marginal Stability and Aggregation in Cells

Cited by 7 publications

References 53 publications

CAG-Repeat RNA Hairpin Folding and Recruitment to Nuclear Speckles with a Pivotal Role of ATP as a Cosolute

CAG-Repeat RNA Hairpin Folding and Recruitment to Nuclear Speckles with a Pivotal Role of ATP as a Cosolute

Identification of Genetic Variants for Diabetic Retinopathy Risk Applying Exome Sequencing in Extreme Phenotypes

Adenylyl-Sulfate Kinase (Met14)-Dependent Cysteine and Methionine Biosynthesis Pathways Contribute Distinctively to Pathobiological Processes in Cryptococcus neoformans

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