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PubMed2025

Enrichment of G-to-U Substitution in SARS-CoV-2 Functional Regions and Its Compensation via Concurrent Mutations.

We surveyed single nucleotide variant (SNV) patterns from 5 903 647 complete SARS-CoV-2 genomes. Among 10 012 SNVs, APOBEC-mediated C-to-U (C > U) deamination was the most prevalent, followed by G > U and other RNA editing-related substitutions including (A > G, U > C, G > A). However, C > U mutations were less frequent in functional regions, for example, S protein, intrinsic disordered regions, and nonsynonymous mutations, where G > U were over-represented. Notably, G-loss substitutions rarely appeared together. Instead, G-gain mutations tended to more frequently co-occur with others, with a marked preference in the S protein, suggesting a compensatory mechanism for G loss in G > U mutations. The temporal patterns revealed C > U frequency declined until late 2021 then resurged in early 2022. Conversely, G > U steadily decreased, with a pronounced drop in January 2022, coinciding with reduced COVID-19 severity. Vaccinated individuals exhibited a slightly but significantly higher C > U frequency and a notably lower G > U frequency compared to the unvaccinated group. Additionally, cancer patients had higher G > U frequency than general patients during the same period. Interestingly, none of the C > U SNVs were uniquely identified in 2724 environmental samples. These findings suggest novel functional roles of G > U in COVID-19 symptoms, potentially linked to oxidative stress and reactive oxygen species, while C > U remains the dominant substitution, likely driven by host immune-mediated RNA editing.

SARS-CoV-2↗

PubMed2004

Combining prediction, computation and experiment for the characterization of protein disorder.

Several computational and experimental methods exist for identifying disordered residues within proteins. Computational algorithms can now identify these disordered sequences and predict their occurrence within genomes with relatively high accuracy. Recent advances in NMR and mass spectroscopy permit faster and more detailed studies of disordered states at atomic resolutions. Combining prediction, computation and experimentation is proposed to accelerate and enhance the characterization of intrinsically disordered protein.

Hydrolysis↗

PubMed2004

The N-terminal domain of the Drosophila histone mRNA binding protein, SLBP, is intrinsically disordered with nascent helical structure.

Stem-loop binding protein (SLBP) is a 31 kDa protein that is central to the regulation of histone mRNAs and is highly conserved in metazoans. In vertebrates, the N-terminal domain of SLBP has sequence determinants necessary for histone mRNA translation, SLBP degradation, cyclin binding, and histone mRNA import. We have used high-resolution NMR spectroscopy and circular dichroism to characterize the structural and dynamic features of this domain of SLBP from Drosophila (dSLBP). We report that the N-terminal domain of dSLBP is stably unfolded but has nascent helical structure at physiological pH and native-like solution conditions. The conformational and dynamic properties of the isolated domain are mimicked in a longer 175-residue region of the N-terminus, as well as in the full-length protein. Complete resonance assignments, secondary structure propensity, and motional properties of a 91-residue N-terminal domain (G17-K108) of dSLBP are reported here. The deviation of (1)H(alpha), (13)C(alpha), and (13)C(beta) chemical shifts from random coil reveals that there are four regions between residues I28-A45, S50-L57, S66-G75, and F91-N96 that have helical propensity. These regions also have small but positive heteronuclear NOEs, interresidue d(NN) NOEs, and small but significant protection from solvent exchange. However the lack of medium- and long-range NOEs in 3D (15)N- and (13)C-edited spectra, fast amide proton exchange rates (all greater than 1 s(-1)), and long (15)N relaxation (T(1), T(2)) times suggest that the domain from dSLBP does not adopt a well-defined tertiary fold. The backbone residual dipolar couplings (RDCs) for this domain are small and lie close to 0 Hz (+/-2 Hz) for most residues with no well-defined periodicity. The implications of this unfolded state for the function of dSLBP in regulating histone metabolism are discussed.

Amino Acid Sequence↗

PubMed2006

Computational models for the prediction of polypeptide aggregation propensity.

In amyloid fibrils, beta-strand conformations of polypeptide chains, or segments thereof, are perpendicular to the fibril axis, but knowledge of their three dimensional structure at atomic level of detail is scarce. Two types of computational approaches have been developed recently for investigating the aggregation propensity of peptides and proteins and identifying the segments most prone to form fibrils (hot spots). The physicochemical properties of the natural amino acids (e.g. beta-propensity, hydrophobicity, aromatic content and charge) have been used to derive phenomenological models able to predict changes in aggregation rate upon mutation, as well as absolute rates and hot spots. Applications of these models to entire proteomes have provided evidence that intrinsically disordered proteins are less amyloidogenic than globular proteins. In the second type of approach, amyloidogenic polypeptides have been decomposed into overlapping segments, and atomistic simulations of three or more copies of each segment have been performed to obtain insights into aggregation propensity and structural details of the ordered aggregates (e.g. turn regions).

Chemical Phenomena↗

PubMed2006

Spectroscopic characterization of the tumor antigen NY-REN-21 and identification of heterodimer formation with SCAND1.

Human NY-REN-21 is a C2H2 type multi-finger protein, with a SCAN domain in the N-terminal region and a predicted coil central region. It represents a putative ortholog of mouse ZFP38, a transcriptional factor that recognizes a bipartite DNA motif and is unable to form homodimers. As shown in this work, NY-REN-21 contains a SCAN domain able to form homodimers and a central region that behaves as an intrinsically disordered protein. The SCAN domain is found in 71 human proteins and its ability to form homo- and heterodimers widens the number of genes that are regulated by this group of transcription factors. NY-REN-21 interaction with SCAND1 was identified using the yeast two-hybrid system and confirmed using recombinant proteins. SCAND1 is a truncated SCAN box protein, lacking the zinc finger region and the NY-REN-21/SCAND1 heterodimer is asymmetric concerning the DNA binding region. This result indicates that NY-REN-21 can function either as a homodimer or as a heterodimer with SCAND1.

Amino Acid Sequence↗

PubMed2006

SMART 5: domains in the context of genomes and networks.

The Simple Modular Architecture Research Tool (SMART) is an online resource (http://smart.embl.de/) used for protein domain identification and the analysis of protein domain architectures. Many new features were implemented to make SMART more accessible to scientists from different fields. The new 'Genomic' mode in SMART makes it easy to analyze domain architectures in completely sequenced genomes. Domain annotation has been updated with a detailed taxonomic breakdown and a prediction of the catalytic activity for 50 SMART domains is now available, based on the presence of essential amino acids. Furthermore, intrinsically disordered protein regions can be identified and displayed. The network context is now displayed in the results page for more than 350 000 proteins, enabling easy analyses of domain interactions.

Catalysis↗

PubMed2003

Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go?

The structure-function paradigm claims that a specific function of a protein is determined by its unique and rigid three-dimensional (3D) structure. Thus, following its biosynthesis on the ribosome, a protein must fold to be functional. This idea represents one of the cornerstones of modern biology. Numerous cases when, due to the effect of environmental factors or because of genetic defects (mutations), a polypeptide chain has lost its capability to gain a proper functional 3D structure (i.e. became misfolded), seem to confirm this concept. Consequences of such misfolding are well known and represent lost of function, aggregation, development of conformational disorders and cell death. However, the recent revelation of countless examples of intrinsically disordered proteins has cast doubt on the general validity of the structure-function paradigm and revealed an intriguing route of functional disorder. Thus, in a living cell, a polypeptide chain chooses between three potential fates - functional folding, potentially deadly misfolding and mysterious nonfolding. This choice is dictated by the peculiarities of amino acid sequence and/or by the pressure of environmental factors. The aim of the present review is to outline some interesting features of these three routes.

Amino Acid Sequence↗

PubMed2006

Analysis of molecular recognition features (MoRFs).

Several proteomic studies in the last decade revealed that many proteins are either completely disordered or possess long structurally flexible regions. Many such regions were shown to be of functional importance, often allowing a protein to interact with a large number of diverse partners. Parallel to these findings, during the last five years structural bioinformatics has produced an explosion of results regarding protein-protein interactions and their importance for cell signaling. We studied the occurrence of relatively short (10-70 residues), loosely structured protein regions within longer, largely disordered sequences that were characterized as bound to larger proteins. We call these regions molecular recognition features (MoRFs, also known as molecular recognition elements, MoREs). Interestingly, upon binding to their partner(s), MoRFs undergo disorder-to-order transitions. Thus, in our interpretation, MoRFs represent a class of disordered region that exhibits molecular recognition and binding functions. This work extends previous research showing the importance of flexibility and disorder for molecular recognition. We describe the development of a database of MoRFs derived from the RCSB Protein Data Bank and present preliminary results of bioinformatics analyses of these sequences. Based on the structure adopted upon binding, at least three basic types of MoRFs are found: alpha-MoRFs, beta-MoRFs, and iota-MoRFs, which form alpha-helices, beta-strands, and irregular secondary structure when bound, respectively. Our data suggest that functionally significant residual structure can exist in MoRF regions prior to the actual binding event. The contribution of intrinsic protein disorder to the nature and function of MoRFs has also been addressed. The results of this study will advance the understanding of protein-protein interactions and help towards the future development of useful protein-protein binding site predictors.

Algorithms↗

PubMed2005

Protein dynamics of bovine dentin phosphophoryn.

Bovine dentin phosphophoryn (BDP), a protein rich in aspartyl (Asp) and o-phosphoseryl [Ser(P)] residues, is synthesized by odontoblasts and believed to be involved in matrix-mediated biomineralization of dentin. The elucidation of the structure-function relationship of phosphophoryn has been a challenge because of its high-molecular weight, high negative charge, repetitive sequence, and lability. We have used the dynamic behavior of the (1)H NMR signal at 600 MHz to provide insight into the molecular dynamics of phosphophoryn. Our results indicate that phosphophoryn is a molecule of uniformly high mobility, thus belonging to a recently identified class of intrinsically disordered proteins that are characterized by sequences of low complexity and rich in polar and charged residues. The significance of our results is that phosphophoryn, because of its uniform nature has the potential to be replaced by biomimetic synthetic peptide analogs that together with amorphous calcium phosphate may lead to the development of novel, nontoxic, apatite-based dental restorative materials.

Amino Acid Motifs↗

PubMed2006

Studies on titin PEVK peptides and their interaction.

Experiments were conducted on several synthetic and expressed peptides from the PEVK region of titin, the giant muscle protein. Different secondary structure prediction methods based on amino acid sequence gave estimates ranging from over 70% alpha helical to no helix (totally disordered) for the polyE peptide corresponding to human exon 115. Circular dichroism (CD) experiments demonstrated that both the positively charged PPAK modules and the negatively charged PolyE repeats had similar spectral properties with disordered secondary structure predominating. Gel permeation chromatography showed that both PPAK and polyE peptides had 2-4 times larger Stokes radii than expected from their molecular mass. Mixtures of the oppositely charged titin peptides caused no change in apparent secondary structure as observed by circular dichroism or migration properties using native gel electrophoresis. Similarly addition of calcium did not alter the CD spectra or peptide electrophoretic mobility of the individual peptides or their mixtures. The properties of both the PPAK and polyE type peptides suggest that both had most of the characteristic properties to be classified as intrinsically disordered proteins.

Amino Acid Sequence↗

PubMed2003

Highly asymmetric interactions between globin chains during hemoglobin assembly revealed by electrospray ionization mass spectrometry.

Dynamics of bovine hemoglobin assembly was investigated by monitoring monomers/oligomers equilibria in solution with electrospray ionization mass spectrometry and circular dichroism spectroscopy. Intensities of ionic signals corresponding to various protein species (tetramers, dimers, heme-deficient dimers, as well as apo- and holo-monomers) were used to estimate relative fractions of these species in solution as a function of pH. The fraction of folded protein for each observed species was estimated based on charge-state distributions of corresponding ionic species in the mass spectra. The cumulative numbers (averaged across the entire protein population) were in good agreement with circular dichroism data at the Soret band and in the far-UV region, respectively. The mass spectral data confirm that hemoglobin dissociation involves a step where heme is first lost from the beta-chain of the alpha beta-dimer to form a heme-deficient dimeric species. This dimer dissociates further to produce a holo-alpha-chain and an apo-beta-chain. The former is tightly folded into a comparatively compact structure at neutral pH, while the latter always exhibits significant backbone disorder. Acidification of the protein solution to pH 4 leads to partial heme dissociation and significant increase of the backbone flexibility in the alpha-chains as well. Complete dissociation of the heme from the alpha-chains at a pH below 4 coincides with the total disappearance of the dimeric and tetrameric hemoglobin species from the mass spectra. The experimental data provide strong evidence that binding of a partially unstructured apo-beta-chain to a tightly folded holo-alpha-chain to form a heme-deficient dimer is the initial step of hemoglobin assembly. Such binding locks the beta-chain in a highly ordered conformation, which allows for an efficient heme acquisition, followed by docking of two hemoglobin dimers to form a tetrameric form of the protein. The asymmetry of the roles of the two chains in the assembly process is surprising, given a rather high sequence homology (ca. 43%) and highlights functional importance of intrinsic protein disorder. The study also demonstrates a tremendous potential of mass spectrometry as an analytical tool capable of elucidating protein interaction mechanisms in highly heterogeneous systems.

Animals↗

PubMed2005

Evaluation of Prader-Willi Syndrome gene MAGEL2 in severe childhood-onset obesity.

MAGEL2 is one of the five genes inactivated in Prader-Willi Syndrome, a neurodevelopmental chromosome microdeletion disorder modified by genomic imprinting. By early childhood, individuals with Prader-Willi Syndrome exhibit hypothalamic dysfunction, including hyperphagia, and become obese in the absence of behavioral intervention. Murine Magel2 is highly expressed in the hypothalamus during development. We screened the MAGEL2 open reading frame for mutations in genomic DNA samples from hyperphagic but non-dysmorphic individuals with severe childhood-onset obesity. Although no mutations likely to affect gene function were identified, we identified three variant alleles. We conclude that severe childhood-onset obesity is not commonly caused by MAGEL2 mutations.

Antigens, Neoplasm↗

PubMed2005

Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth.

Necdin and Magel2 are related proteins inactivated in Prader-Willi syndrome (PWS), a sporadic chromosomal deletion disorder. We demonstrate that necdin and Magel2 bind to and prevent proteasomal degradation of Fez1, a fasciculation and elongation protein implicated in axonal outgrowth and kinesin-mediated transport, and also bind to the Bardet-Biedl syndrome (BBS) protein BBS4 in co-transfected cells. The interactions among necdin, Magel2, Fez1 and BBS4 occur at or near centrosomes. Centrosomal or pericentriolar dysfunction has previously been implicated in BBS and may also be important in the features of PWS that overlap with BBS, such as learning disabilities, hypogonadism and obesity. Morphological abnormalities in axonal outgrowth and fasciculation manifest in several regions of the nervous system in necdin null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic and catecholaminergic neurons. These data demonstrate that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin impinges on axonal outgrowth. We further suggest that loss of necdin contributes to the neurological phenotype of PWS, and raise the possibility that co-deletion of necdin and the related protein Magel2 may explain the lack of single gene mutations in PWS.

Animals↗

PubMed2003

Prader-Willi syndrome transcripts are expressed in phenotypically significant regions of the developing mouse brain.

Prader-Willi syndrome (PWS) is a neurobehavioral disorder that is due to the loss of multiple, paternally-expressed, imprinted genes on human chromosome 15q11-q13. The candidate genes are conserved in mice and are located in an orthologous region on mouse 7C. Several mouse models in which one or more of the PWS candidate genes are silenced do not recapitulate the full PWS phenotype. We examined the expression patterns of the mouse orthologues of PWS candidate genes throughout the development of the brain regions most implicated in PWS, including the hypothalamus, pituitary, forebrain and hindbrain. Snrpn, Ipw and Ndn are widely expressed at high levels throughout the mouse brain, whereas Magel2, Mkrn3 and the snoRNA MBII-85 are preferentially expressed in specific brain regions. Magel2 is most specifically expressed in developing hypothalamus, the region of the brain implicated in PWS hyperphagia and obesity. Although Snrpn, Ipw and MBII-85 are putatively transcribed from the same promoter, the transcripts are differentially detected in neural tissues. The analysis of expression patterns of murine orthologues of human disease genes is valuable for identifying sites of gene expression that correlate with disease phenotype.

Animals↗

PubMed2003

Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor.

Necdin is a growth suppressor expressed predominantly in postmitotic neurons and implicated in their terminal differentiation. Necdin shows a moderate homology to the MAGE family proteins, the functional roles of which are largely unknown. Human genes encoding necdin, MAGEL2 (necdin-like 1), and MAGE-G1 (necdin-like 2) are located in proximal chromosome 15q, a region associated with neurodevelopmental disorders such as Prader-Willi syndrome, Angelman syndrome, and autistic disorder. The necdin and MAGEL2 genes are subjected to genomic imprinting and suggested to be involved in the etiology of Prader-Willi syndrome. In this study, we compared biochemical and functional characteristics of murine orthologs of these necdin-related MAGE proteins. The colony formation and bromodeoxyuridine incorporation analyses revealed that necdin and MAGE-G1, but not MAGEL2, induced growth arrest. Necdin and MAGE-G1 interacted with the transcription factor E2F1 via its transactivation domain, repressed E2F1-dependent transcription, and antagonized E2F1-induced apoptosis of N1E-115 neuroblastoma cells. In addition, necdin and MAGE-G1 interacted with the p75 neurotrophin receptor via its distinct intracellular domains. In contrast, MAGEL2 failed to bind to these necdin interactors, suggesting that MAGEL2 has no necdin-like function in developing brain. Overexpression of p75 translocated necdin and MAGE-G1 in the proximity of the plasma membrane and reduced their association with E2F1 to facilitate E2F1-induced death of neuroblastoma cells. These results suggest that necdin and MAGE-G1 target both E2F1 and p75 to regulate cell viability during brain development.

Animals↗

PubMed1999

The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region.

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder. The phenotype is likely to be a contiguous gene syndrome involving genes which are paternally expressed only, located in the human 15q11-q13 region. Four mouse models of PWS have been reported but these do not definitively allow the delineation of the critical region and the associated genes involved in the aetiology of PWS. Moreover, targeted mutagenesis of mouse homologues of the human candidate PWS genes does not appear to result in any of the features of PWS. Therefore, the isolation of new genes in this region remains crucial for a better understanding of the molecular basis of PWS. In this manuscript, we report the characterization of MAGEL2 and its mouse homologue Magel2. These are located in the human 15q11-q13 and mouse 7C regions, in close proximity to NDN / Ndn. By northern blot analysis we did not detect any expression of MAGEL2 / Magel2 but by RT-PCR analysis, specific expression was detected in fetal and adult brain and in placenta. Both genes are intronless with tandem direct repeat sequences contained within a CpG island in the 5'-untranscribed region. The transcripts encode putative proteins that are homologous to the MAGE proteins and NDN. Moreover, MAGEL2 / Magel2 are expressed only from the paternal allele in brain, suggesting a potential role in the aetiology of PWS and its mouse model, respectively.

5' Untranslated Regions↗

PubMed2000

Identification of a testis-specific gene (C15orf2) in the Prader-Willi syndrome region on chromosome 15.

Prader-Willi syndrome (PWS) results from the loss of paternal contributions for a 2-Mb imprinted region on the proximal long arm of human chromosome 15. Hitherto, five paternally active genes have been identified in this region (ZNF127, NDN, MAGEL2, SNURF-SNRPN, and IPW). Here we report the identification of a novel gene in the PWS critical region, which has been designated "chromosome 15 open reading frame 2" (C15orf2). C15orf2 is an intronless gene located between MAGEL2 and SNURF-SNRPN. It is associated with a CpG island, which is methylated in all tissues tested except for germ cells. C15orf2 is transcribed as a 7.5-kb mRNA and contains an open reading frame encoding a predicted 1156-amino-acid protein of unknown function. Transcription of C15orf2 occurs exclusively in the testis, and in adult testis samples, we observed biallelic expression. By zoo-blot analysis, we found related sequences in DNA from other primates, but not in nonprimate DNA. We conclude that C15orf2 may play a role in primate spermatogenesis.

3' Untranslated Regions↗

PubMed2005

Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.

The intrinsically disordered protein alpha-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD). We show here that the native state of alpha-synuclein consists of a broad distribution of conformers with an ensemble-averaged hydrodynamic radius significantly smaller than that expected for a random coil structure. This partial condensation is driven by interactions between the highly charged C-terminus and a large hydrophobic central region of the protein sequence. We suggest that this structure could inhibit the formation of alpha-synuclein aggregates, which are thought to be the cytotoxic species responsible for neurodegeneration in PD.

Computer Simulation↗