Methyltransferase-like protein 16 (METTL16) is a human RNA methyltransferase that installs m
A marks on U6 small nuclear RNA (U6 snRNA) and
-adenosylmethionine (SAM) synthetase pre-mRNA. METTL16 also ...controls a significant portion of m
A epitranscriptome by regulating SAM homeostasis. Multiple molecular structures of the N-terminal methyltransferase domain of METTL16, including apo forms and complexes with
-adenosylhomocysteine (SAH) or RNA, provided the structural basis of METTL16 interaction with the coenzyme and substrates, as well as indicated autoinhibitory mechanism of the enzyme activity regulation. Very recent structural and functional studies of vertebrate-conserved regions (VCRs) indicated their crucial role in the interaction with U6 snRNA. METTL16 remains an object of intense studies, as it has been associated with numerous RNA classes, including mRNA, non-coding RNA, long non-coding RNA (lncRNA), and rRNA. Moreover, the interaction between METTL16 and oncogenic lncRNA MALAT1 indicates the existence of METTL16 features specifically recognizing RNA triple helices. Overall, the number of known human m
A methyltransferases has grown from one to five during the last five years. METTL16, CAPAM, and two rRNA methyltransferases, METTL5/TRMT112 and ZCCHC4, have joined the well-known METTL3/METTL14. This work summarizes current knowledge about METTL16 in the landscape of human m
A RNA methyltransferases.
N
-methyladenosine (m
A) is an abundant modification in messenger RNA and noncoding RNAs that affects RNA metabolism. Methyltransferase-like protein 16 (METTL16) is a recently confirmed m
A RNA ...methyltransferase that methylates U6 spliceosomal RNA and interacts with the 3'-terminal RNA triple helix of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1). Here, we present two X-ray crystal structures of the N-terminal methyltransferase domain (residues 1-291) of human METTL16 (METTL16_291): an apo structure at 1.9 Å resolution and a post-catalytic S-adenosylhomocysteine-bound complex at 2.1 Å resolution. The structures revealed a highly conserved Rossmann fold that is characteristic of Class I S-adenosylmethionine-dependent methyltransferases and a large, positively charged groove. This groove likely represents the RNA-binding site and it includes structural elements unique to METTL16. In-depth analysis of the active site led to a model of the methyl transfer reaction catalyzed by METTL16. In contrast to the major m
A methyltransferase heterodimer METTL3/METTL14, full-length METTL16 forms a homodimer and METTL16_291 exists as a monomer based on size-exclusion chromatography. A native gel-shift assay shows that METTL16 binds to the MALAT1 RNA triple helix, but monomeric METTL16_291 does not. Our results provide insights into the molecular structure of METTL16, which is distinct from METTL3/METTL14.
In this qualitative study, I offer a feminist reflection on motherhood from the perspectives of 25 women with various types of physical and sensory disabilities. Disability was treated not only as an ...individual experience but also as a social construct. I conducted 25 non-standardised narrative interviews with women with various types of physical disabilities. Using grounded theory method, with a particular emphasis on symbolic interactionism, I identified three important themes from the non-standardised narrative interviews: the effects of insufficient health care on pregnant women, the lack of acceptance and support for mothers, and a welfare system inadequate to the needs of mothers. These themes affect the way Polish women with disabilities experience motherhood. Findings highlight the different ways that mothers with disabilities challenge the prevailing normative categories of gender and disability and, in so doing, demythologise and delegitimise the traditional Polish model of motherhood. While this study points to needed reforms in Poland to support women with disabilities, it also reveals a model of motherhood based on interdependence and mutual care. The women with disabilities in this study identify new possibilities for all families.
The chemical identity of RNA molecules beyond the four standard ribonucleosides has fascinated scientists since pseudouridine was characterized as the “fifth” ribonucleotide in 1951. Since then, the ...ever‐increasing number and complexity of modified ribonucleosides have been found in viruses and throughout all three domains of life. Such modifications can be as simple as methylations, hydroxylations, or thiolations, complex as ring closures, glycosylations, acylations, or aminoacylations, or unusual as the incorporation of selenium. While initially found in transfer and ribosomal RNAs, modifications also exist in messenger RNAs and noncoding RNAs. Modifications have profound cellular outcomes at various levels, such as altering RNA structure or being essential for cell survival or organism viability. The aberrant presence or absence of RNA modifications can lead to human disease, ranging from cancer to various metabolic and developmental illnesses such as Hoyeraal–Hreidarsson syndrome, Bowen–Conradi syndrome, or Williams–Beuren syndrome. In this review article, we summarize the characterization of all 143 currently known modified ribonucleosides by describing their taxonomic distributions, the enzymes that generate the modifications, and any implications in cellular processes, RNA structure, and disease. We also highlight areas of active research, such as specific RNAs that contain a particular type of modification as well as methodologies used to identify novel RNA modifications.
This article is categorized under:
RNA Processing > RNA Editing and Modification
Adenosine, guanosine, cytidine, and uridine can be modified at various positions (red) with a myriad of functional groups (outside circle).
Background
Little is known about the experience of growing up with a mother with intellectual disability. The aim of this study was to explore this experience from the perspective of adult children.
...Method
In‐depth interviews with 23 adult children brought up by mothers with moderate‐to‐severe intellectual disability. The interview data were analysed using grounded theory methods.
Results
The childhood experiences of the interviewees and the role their mothers played in their upbringing varied, depending in part on the involvement of extended family. It was the stigma of maternal intellectual disability, rather than their mother's functional limitations, that posed the greatest challenge.
Conclusion
Interviewees characterized their mothers and childhoods as different, yet ordinary. Understanding the social context, including but not limited to the availability of informal support, is critical to understanding the experience of children growing up with mothers with intellectual disability.
Serine hydroxymethyltransferase (SHMT, EC 2.1.2.1) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme which catalyzes the reversible serine-to-glycine conversion in either a ...tetrahydrofolate-dependent or -independent manner. The enzyme is also responsible for the tetrahydrofolate-independent cleavage of other β-hydroxy amino acids. In addition to being an essential player in the serine homeostasis, SHMT action is the main source of activated one-carbon units, which links SHMT activity with the control of cell proliferation. In plants, studies of SHMT enzymes are more complicated than of those of, e.g., bacterial or mammalian origins because plant genomes encode multiple SHMT isozymes that are targeted to different subcellular compartments: cytosol, mitochondria, plastids, and nucleus. Here we report crystal structures of chloroplast-targeted SHMT from
(
SHMT3).
SHMT3 is a tetramer in solution, composed of two tight and obligate dimers. Our complexes with PLP internal aldimine, PLP-serine and PLP-glycine external aldimines, and PLP internal aldimine with a free glycine reveal structural details of the
SHMT3-catalyzed reaction. Capturing the enzyme in different stages along the course of the slow tetrahydrofolate-independent serine-to-glycine conversion allowed to observe a unique conformation of the PLP-serine γ-hydroxyl group, and a concerted movement of two tyrosine residues in the active site.
Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, ...5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria-human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics.
Influenza A is a negative sense RNA virus that kills hundreds of thousands of humans each year. Base pairing in RNA is very favorable, but possibilities for RNA secondary structure of the influenza ...genomic RNA have not been investigated. This work presents the first experimentally-derived exploration of potential secondary structure in an influenza A naked (protein-free) genomic segment. Favorable folding regions are revealed by in vitro chemical structure mapping, thermodynamics, bioinformatics, and binding to isoenergetic microarrays of an entire natural sequence of the 875 nt segment 8 vRNA and of a smaller fragment. Segment 8 has thermodynamically stable and evolutionarily conserved RNA structure and encodes essential viral proteins NEP and NS1. This suggests that vRNA self-folding may generate helixes and loops that are important at one or more stages of the influenza life cycle.
The main goal of this study was to identify the impact of a narrative construction of a life challenge - discovering to have a child with autism - on the meaning of life and on resources for coping ...depending on the challenge's novelty, i.e., the number of years from the diagnosis. Three hundred and sixty four mothers of children with autism participated in a long-term 3 × 2 experiment. Half of the mothers had children with autism at the age of 9-12 years. For the remaining half, having children with autism was a new and stressful life situation. Their children were 2-3 years old and just diagnosed by a medical center as having autism spectrum disorder. The mothers were assigned to one of three study conditions: they were either asked to write stories of their motherhood or to describe their children's behavior on a questionnaire or they did not participate in any tasks. One month and then 4 months after this task the participants completed measures of meaning of life and several well-being scales. The results indicated that following the narrative writing the participants had the highest scores on the meaning of life and well-being scales. This affect was sustained over 4 months and was significant only for mothers with older children. The mediation analysis showed that the effects of the experimental conditions on different well-being scales were mediated by the changes in perceived meaning of life. The results suggest that construction of self-narratives of difficult ongoing challenges facilitates meaning making and subsequently strengthens resources for coping. However, it seems that a meaning-making construction of such self-story may be blocked by the uncertainty and stress caused by novelty of the challenging situation.
SARS-CoV-2 belongs to the
family. Like other coronaviruses, SARS-CoV-2 is enveloped and possesses a positive-sense, single-stranded RNA genome of ~30 kb. Genomic RNA is used as the template for ...replication and transcription. During these processes, positive-sense genomic RNA (gRNA) and subgenomic RNAs (sgRNAs) are created. Several studies presented the importance of the genomic RNA secondary structure in SARS-CoV-2 replication. However, the structure of sgRNAs has remained largely unsolved so far. In this study, we probed the sgRNA M model of SARS-CoV-2 in vitro. The presented model molecule includes 5'UTR and a coding sequence of gene M. This is the first experimentally informed secondary structure model of sgRNA M, which presents features likely to be important in sgRNA M function. The knowledge of sgRNA M structure provides insights to better understand virus biology and could be used for designing new therapeutics.
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