Showing papers by "Tammo Diercks published in 2019"
TL;DR: A non-invasive and readily accessible urine sample contains enough information to assess the potential existence of a substantial number of IEMs in newborns, using a single, automated and standardized 1H- NMR-based analysis.
Abstract: Inborn errors of metabolism (IEMs) are rare diseases produced by the accumulation of abnormal amounts of metabolites, toxic to the newborn. When not detected on time, they can lead to irreversible physiological and psychological sequels or even demise. Metabolomics has emerged as an efficient and powerful tool for IEM detection in newborns, children, and adults with late onset. In here, we screened urine samples from a large set of neonates (470 individuals) from a homogeneous population (Basque Country), for the identification of congenital metabolic diseases using NMR spectroscopy. Absolute quantification allowed to derive a probability function for up to 66 metabolites that adequately describes their normal concentration ranges in newborns from the Basque Country. The absence of another 84 metabolites, considered abnormal, was routinely verified in the healthy newborn population and confirmed for all but 2 samples, of which one showed toxic concentrations of metabolites associated to ketosis and the other one a high trimethylamine concentration that strongly suggested an episode of trimethylaminuria. Thus, a non-invasive and readily accessible urine sample contains enough information to assess the potential existence of a substantial number (>70) of IEMs in newborns, using a single, automated and standardized 1H- NMR-based analysis.
28 citations
TL;DR: The crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP), are presented and it is found that only the Batemen module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity.
Abstract: The four member family of “Cyclin and Cystathionine β-synthase (CBS) domain divalent metal cation transport mediators”, CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.
15 citations
TL;DR: This work presents an NMR conformational characterization of p15PAF monoubiquitinated at both K15 and K24 via a disulfide bridge mimicking the isopeptide bond and shows that the ubiquitin moieties, separated by 8 disordered residues, form transient dimers due to the high local effective concentration.
Abstract: The proliferating cell nuclear antigen (PCNA)-associated factor p15PAF is a nuclear protein that acts as a regulator of DNA repair during DNA replication. The p15PAF gene is overexpressed in severa...
14 citations
TL;DR: A new 77Se NMR spectroscopy method is presented for complementary studies of selenoglycans with optimised resolution and sensitivity, in which direct NMR spectrometry detection on 77Se is replaced by its indirect observation in a 2D 1H,77Se HSQMBC spectrum.
Abstract: The fundamental importance of protein-glycan recognition calls for specific and sensitive high-resolution techniques for their detailed analysis. After the introduction of 19 F NMR spectroscopy to study the recognition of fluorinated glycans, a new 77 Se NMR spectroscopy method is presented for complementary studies of selenoglycans with optimised resolution and sensitivity, in which direct NMR spectroscopy detection on 77 Se is replaced by its indirect observation in a 2D 1 H,77 Se HSQMBC spectrum. In contrast to OH/F substitution, O/Se exchange allows the glycosidic bond to be targeted. As an example, selenodigalactoside recognition by three human galectins and a plant toxin is readily indicated by signal attenuation and line broadening in the 2D 1 H,77 Se HSQMBC spectrum, in which CPMG-INEPT long-range transfer ensures maximal detection sensitivity, clean signal phases, and reliable ligand ranking. By monitoring competitive displacement of a selenated spy ligand, the selective 77 Se NMR spectroscopy approach may also be used to screen non-selenated compounds. Finally, 1 H,77 Se CPMG-INEPT transfer allows further NMR sensors of molecular interaction to be combined with the specificity and resolution of 77 Se NMR spectroscopy.
9 citations
TL;DR: In this paper, the conformation of the polyQ tract of the androgen receptor (AR), a transcription factor associated with polyQ disease spinobulbar muscular atrophy (SBMA), depends on its length.
Abstract: Polyglutamine (polyQ) tracts are regions of low sequence complexity of variable length found in more than one hundred human proteins. These tracts are frequent in activation domains of transcription factors and their length often correlates with transcriptional activity. In addition, in nine proteins, tract elongation beyond specific thresholds causes polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, here we addressed how the conformation of the polyQ tract of the androgen receptor (AR), a transcription factor associated with the polyQ disease spinobulbar muscular atrophy (SBMA), depends on its length. We found that the tract folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups. These bonds are bifurcate with the conventional main chain to main chain hydrogen bonds stabilizing α-helices. In addition, since tract elongation provides additional interactions, the helicity of the polyQ tract directly correlates with its length. These findings suggest a plausible rationale for the association between polyQ tract length and AR transcriptional activity and have implications for establishing the mechanistic basis of SBMA.