Disease relevance of asparagine

• The 2.0 A resolution structure of Escherichia coli DksA reveals a globular domain and a coiled coil with two highly conserved Asp residues at its tip that is reminiscent of the transcript cleavage factor GreA [1].
• Two mutations in this domain, Asp 47----Glu, and Asp 64----Asn, present in patients with haemophilia B, reduce calcium binding to the domain greater than 4-fold and greater than 1,000-fold, respectively [2].
• Mice bearing the Asp mutation in the serine 191 phosphorylation site are runted and anemic and display splenomegaly [3].
• The products of the human leukocyte antigen subtypes HLA-B*2705 and HLA-B*2709 differ only in residue 116 (Asp vs. His) within the peptide binding groove but are differentially associated with the autoimmune disease ankylosing spondylitis (AS); HLA-B*2705 occurs in AS-patients, whereas HLA-B*2709 does not [4].
• Mastocytosis is often associated with a somatic point mutation in the Kit protooncogene leading to an Asp/Val substitution at position 816 in the kinase domain of this receptor [5].

Psychiatry related information on asparagine

• In a functional presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity [6].
• An association study was performed between apolipoprotein E (apoE) polymorphism and the common structural polymorphism Glu/Asp at codon 298 of the nitric oxide synthase (NOS3) gene in late-onset sporadic Alzheimer's dementia probands (LOAD), diffuse Lewy body dementia cases (DLBD) and controls in a Hungarian sample [7].

High impact information on asparagine

• Biochemical analysis demonstrates that DksA affects transcript elongation, albeit differently from GreA; augments ppGpp effects on initiation; and binds directly to RNAP, positioning the Asp residues near the active site [1].
• We conclude that substitution of the uncharged Asn or Tyr for the acidic Asp at residue 187 creates a conformation that may be preferentially amyloidogenic for GSN [8].
• We found the same mutation in a Dutch family but a Danish FAF family had a G654T mutation, predicting Asp to Tyr at residue 187 [8].
• Accordingly, we expressed in L cells mutant uvomorulin with a replacement of Asp to Lys or Ala [9].
• Site-specific deletion of the putative recognition sequence Arg-Gly-Asp-Ser or an Asp-to-Glu mutation decreased the adhesive activity of fibronectin fusion proteins expressed in E. coli by greater than or equal to 97% [10].

Chemical compound and disease context of asparagine

• The defective binding of apolipoprotein (apo) E2 to lipoprotein receptors, an underlying cause of type III hyperlipoproteinemia, results from replacement of Arg 158 with Cys, disrupting the naturally occurring salt bridge between Asp 154 and Arg 158 [11].
• The unstable hemoglobin Montreal with a deletion of three amino acid residues (Asp, Gly, Leu) at positions 73, 74, and 75 of the beta chain and an insertion of four residues (Ala, Arg, Cys, Gln) at the same location was observed in a 7-year-old Canadian boy suffering from a moderate hemolytic anemia [12].
• In the present study we assess the ability of Aspergillus crude culture filtrate Ags and the recombinant allergen Asp f 2 to induce protective antifungal responses in mice with invasive pulmonary aspergillosis [13].
• Modification of the carboxylate functions of Asp, Asp, and of the COOH-terminal Gln with glycine ethyl ester in the presence of a soluble carbodiimide completely abolished the toxicity but left the affinity for the sea anemone toxin receptor unchanged [14].
• This includes notably two consecutive Asp residues from the phosphoenolpyruvate carboxykinase active site, whose equivalent residues were mutated in Bacillus subtilis HprK/P [15].

Biological context of asparagine

• Alteration of Glu 309, Glu 771, Asn 796, Thr 799, Asp 800 or Glu 908, each of which is predicted to lie near the centre of the transmembrane domain in putative transmembrane sequences M4, M5, M6 and M8 resulted in complete loss of Ca2+ transport function and of Ca2+-dependent phosphorylation of the enzyme by ATP [16].
• A highly conserved residue, Asp 87, positioned within a putative nucleotide-binding pocket in the top of the equatorial domain, is essential for ATP hydrolysis and polypeptide release [17].
• The molecular basis for the little (lit) mouse phenotype, characterized by a hypoplastic anterior pituitary gland, is the mutation of a single nucleotide that alters Asp 60 to Gly in the growth hormone releasing factor receptor [18].
• The nucleotide sequence codes for two amino acids, Met-Cys, preceding the known N-terminal Asp of the mature protein [19].
• The NOD mouse does not express I-E owing to a deletion in the promoter region of the I-E alpha-chain gene, and the sequence of NOD I-A beta-chain in the first external domain is unique with His 56 and Ser 57 replacing Pro and Asp, respectively, at these positions [20].

Anatomical context of asparagine

• Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers [21].
• Thus, Asp appears to hold together the microtubule-nucleating gamma-tubulin ring complexes that organize the mitotic centrosome [21].
• Removing Asp protein function from Drosophila melanogaster embryo extracts, either by mutation or immunodepletion, resulted in loss of their ability to restore microtubule-organizing center activity to salt-stripped centrosome preparations [21].
• To examine T cell reactivity to Af antigens, T cell clones (TCC) specific to the Asp f 1 antigen, an 18-kD protein of Af, were established from the peripheral blood of three ABPA patients [22].
• Replacement of SNAP-25 in PC12 cells with SNAP-25 containing C-terminal Asp mutations led to a loss-of-function in regulated exocytosis at the Ca2+-dependent fusion step [23].

Associations of asparagine with other chemical compounds

• More interestingly, it also reveals the substitution of an Asp residue always found in the serine protease active site triad (Asp, His, Ser) by a Leu residue [24].
• Our X-ray crystallographic studies show that the hydroxyl group of Ser 93 beta forms a hydrogen bond with Asp 94 beta which is in equilibrium with the salt bridge between Asp 94 beta and His 146 beta [25].
• At pH 7.0, reduction of Fe(III) to Fe(II) in the Glu and Asp mutants is accompanied by uptake of a proton by the protein [26].
• The proposal that the absorption maximum of the visual pigments is governed by interaction of the 11-cis-retinal chromophore with charged carboxylic acid side chains in the membrane-embedded regions of the proteins has been tested by mutating five Asp and Glu residues thought to be buried in rhodopsin [27].
• The majority of TCC isolated from ABPA patients, and specific for the Asp f 1 allergen of Af, are IL-4 producing CD4+ cells of the Th2 phenotype [22].

Gene context of asparagine

• Either of the Asp --> Ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6 --> TM7 cytoplasmic loop [6].
• Here, we identified MITF as a new substrate of caspases and we characterized the cleavage site after Asp 345 in the C-terminal domain [28].
• Competition experiments using single Ala-substituted peptides indicated that amino acid residues Asp in position 3 and Tyr in position 9 were essential for binding of the MAGE-1 peptide to HLA-A1 [29].
• Replacement of TF's cytoplasmic Ser residues with Asp to mimic phosphorylation enhances the interaction with ABP-280, whereas Ala mutations abolish coprecipitation of ABP-280 with immobilized TF cytoplasmic domain, and severely reduce cell spreading [30].
• We show that some mutant IL-2 proteins with substitutions of a critical Asp residue in the N-terminal alpha-helix bind the mutant IL-2R beta receptor with a higher affinity than the wild-type receptor [31].

Analytical, diagnostic and therapeutic context of asparagine

• Mutation of Gly74 to Asp at this site, concomitant with considerable changes in the local ordered water structures, contributes to the lack of productive interaction with the transmembrane signal transducer [32].
• We identified a full-length cDNA clone in the dbEST data base, of which the predicted amino acid sequence has extensive homology to other mammalian and bacterial neuraminidases, including the F(Y)RIP domain and "Asp-boxes." In situ hybridization localized the human neuraminidase gene to chromosome band 6p21, a region known to contain the HLA locus [33].
• Crossinhibition radioimmunoassay using murine monoclonal antibody and human IgG and IgE antibodies showed that Asp fI and mitogillin were antigenically indistinguishable [34].
• The cGMP binding site of the phosphodiesterase GAF domain was identified by homology modeling and site-directed mutagenesis, and consists of conserved Arg, Asn, Lys and Asp residues [35].
• Immunofluorescence studies show that the wild-type Asp protein is localized to the polar regions of the spindle immediately surrounding the centrosome [36].

References