5 research outputs found
Association of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with coronary artery disease (CAD) in a North Indian population
There is significant variation in reported associations of the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and coronary artery disease (CAD) in different global populations. This study aims to identify any individual or combined associations between the 1298 and 677 loci of MTHFR and CAD in a North Indian population. A total of 159 patients and 166 controls were genotyped using validated TaqMan assays. Odds ratio analysis identified associations at crude level and multiple logistic regression controlled for confounding variables. Linkage disequilibrium between the loci was assessed along with haplotype association analysis. At the C677T locus, homozygosity of the T allele identified a significantly protective association (OR = 0.38, CI: 0.24–0.60). For the A1298C locus the AC genotype had a protective effect in codominant model (OR = 0.53, CI: 0.32–0.85) and CC genotype showed a susceptible association in recessive model when controlled for age, sex and lipids (OR = 2.70, CI: 1.27–5.77). This study identified that, independently, both heterozygous genotypes show a protective association with CAD. In addition the CC genotype of A1298C in recessive model was a susceptible genotype. The combined associations of MTHFR are protective (primarily due to the effects of C677T locus) suggesting an interaction between the loci and their associations with CAD within this sample
Recognition of proximally phosphorylated tyrosine residues and continuous analysis of phosphatase activity using a stable europium complex
<p>The recognition of proteins and their post-translational modifications using synthetic molecules is an active area of research. A common post-translational modification is the phosphorylation of serine, threonine or tyrosine residues. The phosphorylation of proximal tyrosine residues occurs in over 1000 proteins in the human proteome, including in disease-related proteins, so the recognition of this motif is of particular interest. We have developed a luminescent europium(III) complex, <b>[Eu.1]</b>
<sup><b>+</b></sup>, capable of the discrimination of proximally phosphorylated tyrosine residues, from analogous mono- and non-phosphorylated tyrosine residues, more distantly-related phosphotyrosine residues and over proximally phosphorylated serine and threonine residues. <b>[Eu.1]</b>
<sup><b>+</b></sup> was used to continuously monitor the phosphatase catalysed dephosphorylation of a peptide containing proximally phosphorylated tyrosine residues.</p
Transmembrane Transport of Inorganic Phosphate by a Strapped Calix[4]pyrrole
Synthetic anion receptors are increasingly being explored
for the
transport of anions across lipid membranes because of their potential
therapeutic applications. A considerable amount of research focuses
on the transport of chloride, whereas the transmembrane transport
of inorganic phosphate has not been reported to date, despite the
biological relevance of this anion. Here we present a calix[4]pyrrole
with a bisurea strap that functions as a receptor and transporter
for H2PO4–, relying on the
formation of eight hydrogen bonds and efficient encapsulation of the
anion. Using a phosphate-sensitive lanthanide probe and 31P NMR spectroscopy, we demonstrate that this receptor can transport
phosphate into vesicles by H2PO4–/Cl– antiport, H2PO4– uniport, and Cs+/H2PO4– symport mechanisms. This first example of inorganic
phosphate transport by a neutral receptor opens perspectives for the
future development of transporters for various biological phosphates
Transmembrane Transport of Inorganic Phosphate by a Strapped Calix[4]pyrrole
Synthetic anion receptors are increasingly being explored
for the
transport of anions across lipid membranes because of their potential
therapeutic applications. A considerable amount of research focuses
on the transport of chloride, whereas the transmembrane transport
of inorganic phosphate has not been reported to date, despite the
biological relevance of this anion. Here we present a calix[4]pyrrole
with a bisurea strap that functions as a receptor and transporter
for H2PO4–, relying on the
formation of eight hydrogen bonds and efficient encapsulation of the
anion. Using a phosphate-sensitive lanthanide probe and 31P NMR spectroscopy, we demonstrate that this receptor can transport
phosphate into vesicles by H2PO4–/Cl– antiport, H2PO4– uniport, and Cs+/H2PO4– symport mechanisms. This first example of inorganic
phosphate transport by a neutral receptor opens perspectives for the
future development of transporters for various biological phosphates
Sulfopeptide Probes of the CXCR4/CXCL12 Interface Reveal Oligomer-Specific Contacts and Chemokine Allostery
Tyrosine
sulfation is a post-translational modification that enhances
protein–protein interactions and may identify druggable sites
in the extracellular space. The G protein-coupled receptor CXCR4 is
a prototypical example with three potential sulfation sites at positions
7, 12, and 21. Each receptor sulfotyrosine participates in specific
contacts with its chemokine ligand in the structure of a soluble,
dimeric CXCL12:CXCR4(1–38) complex, but their relative importance
for CXCR4 binding and activation by the monomeric chemokine remains
undefined. NMR titrations with short sulfopeptides showed that the
tyrosine motifs of CXCR4 varied widely in their contributions to CXCL12
binding affinity and site specificity. Whereas the Tyr21 sulfopeptide
bound the same site as in previously solved structures, the Tyr7 and
Tyr12 sulfopeptides interacted nonspecifically. Surprisingly, the
unsulfated Tyr7 peptide occupied a hydrophobic site on the CXCL12
monomer that is inaccessible in the CXCL12 dimer. Functional analysis
of CXCR4 mutants validated the relative importance of individual CXCR4
sulfotyrosine modifications (Tyr21 > Tyr12 > Tyr7) for CXCL12
binding
and receptor activation. Biophysical measurements also revealed a
cooperative relationship between sulfopeptide binding at the Tyr21
site and CXCL12 dimerization, the first example of allosteric behavior
in a chemokine. Future ligands that occupy the sTyr21 recognition
site may act as both competitive inhibitors of receptor binding and
allosteric modulators of chemokine function. Together, our data suggests
that sulfation does not ubiquitously enhance complex affinity and
that distinct patterns of tyrosine sulfation could encode oligomer
selectivity, implying another layer of regulation for chemokine signaling