Disease relevance of WARS

• To study the recognition by tryptophanyl-tRNA synthetase (TrpRS) of tRNA(Trp) discriminator base, mutations were introduced into the discriminator base of Bacillus subtilis, Archeoglobus fulgidus, and bovine tRNA(Trp), representing the three biological domains [1].
• T2-hTrpRS shares a very low sequence homology of 22% with Bacillus stearothermophilus TrpRS (bTrpRS); however, their overall structures are strikingly similar [2].
• Monoclonal antibody Am1 against conservative epitope of tryptophanyl-tRNA synthetase (WRS) was labeled with colloidal gold particles and used to localize the enzyme on ultrathin sections of eubacteria (Escherichia coli), archaebacteria (Methanococcus halophilus), rat pancreas tissue and rat fibroblasts (cell line RAT1) [3].
• Bartonella (formerly Rochalimaea) quintana is the etiological agent of trench fever, a disease extensively reported during the World Wars [4].
• We report that the complex between Deinococcus radiodurans NOS (deiNOS) and an unusual tryptophanyl-tRNA synthetase (TrpRS II) catalyzes the regioselective nitration of tryptophan (Trp) at the 4-position [5].

Psychiatry related information on WARS

• METHODS: Subjects were US military combat veterans of the Vietnam and Gulf Wars recruited from two metropolitan areas served by allied Department of Veterans Affairs PTSD treatment/research centers [6].
• Atherosclerosis during periods of food deprivation following World Wars I and II [7].
• Mapping and molecular characterization of novel monoclonal antibodies to conformational epitopes on NH2 and COOH termini of mammalian tryptophanyl-tRNA synthetase reveal link of the epitopes to aggregation and Alzheimer's disease [8].

High impact information on WARS

• We deleted the anticodon binding domain from tryptophanyl-tRNA synthetase and fused the discontinuous segments comprising its active site [9].
• A Minimal TrpRS Catalytic Domain Supports Sense/Antisense Ancestry of Class I and II Aminoacyl-tRNA Synthetases [9].
• Fragments of TyrRS stimulate angiogenesis, whereas those of TrpRS (T2-TrpRS) inhibit angiogenesis [10].
• In particular, an N-terminally truncated fragment, T2-TrpRS, that is closely related to a natural splice variant is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in several in vivo models [11].
• These results demonstrate that T2-TrpRS can regulate extracellular signal-activated protein kinase, Akt, and EC NO synthase activation pathways that are associated with angiogenesis, cytoskeletal reorganization, and shear stress-responsive gene expression [11].

Biological context of WARS

• A natural fragment, herein designated as mini TrpRS, was shown by others to be produced by alternative splicing [12].
• The splice variant form (mini TrpRS) functions in vascular endothelial cell apoptosis as an angiostatic cytokine [13].
• Human tyrosyl- and tryptophanyl-tRNA synthetases (TyrRS and TrpRS, respectively) link protein synthesis to signal-transduction pathways, including angiogenesis [10].
• A crystal structure of human tryptophanyl-tRNA synthetase was solved at 2.1 A with a tryptophanyl-adenylate bound at the active site [14].
• Thus, this biological fragment of TrpRS may have a role in the maintenance of vascular homeostasis [11].

Anatomical context of WARS

• Interferon induces tryptophanyl-tRNA synthetase expression in human fibroblasts [15].
• We have mapped a cDNA probe of the tryptophanyl-tRNA synthetase gene (WARS) by a combination of somatic cell hybrid analysis, fluorescence in situ hybridization (FISH), and linkage analysis [16].
• HeLa cell DNA polymerase alpha is tightly associated with tryptophanyl-tRNA synthetase and diadenosine 5',5"'-P1,P4-tetraphosphate binding activities [17].
• Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells [18].
• Gamma interferon potently induces tryptophanyl-tRNA synthetase expression in human keratinocytes [19].

Associations of WARS with chemical compounds

• When B. subtilis, A. fulgidus, and human TrpRS were used to acylate these tRNA(Trp), two distinct preference profiles regarding the discriminator base of different tRNA(Trp) substrates were found: G>A>U>C for B. subtilis TrpRS, and A>C>U>G for A. fulgidus and human TrpRS [1].
• These similarities suggest that conserved residues in TrpRS may be responsible for both determining tryptophan recognition and discrimination against tyrosine [20].
• 2.9 A crystal structure of ligand-free tryptophanyl-tRNA synthetase: domain movements fragment the adenine nucleotide binding site [21].
• The dimeric structure (R = 23.7, Rfree = 26.2) is asymmetric, unlike that of the TrpRS tryptophanyl-5'AMP complex (TAM; Doublié S, Bricogne G, Gilmore CJ, Carter CW Jr, 1995, Structure 3:17-31) [21].
• A potential polymorphic variant of human tryptophanyl-tRNA synthetase is shown here to sequester tryptophanyl adenylate [22].

Physical interactions of WARS

• Furthermore, the association of alpha polymerase with either Ap4A-binding protein or tryptophanyl-tRNA synthetase in vivo has not been conclusively demonstrated [23].

Regulatory relationships of WARS

• Functional studies demonstrate that both annexin II and S100A10 regulate trafficking of TrpRS [24].

Other interactions of WARS

• In particular, adaptations to the anticodon recognition domain of TyrRS cause distinct appended domains in TyrRS and TrpRS to occupy the same 3D space and thus to mask a common surface on each synthetase [25].
• Modulation of cellular tryptophan metabolism in human fibroblasts by transforming growth factor-beta: selective inhibition of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA synthetase gene expression [26].
• For four genes [human cartilage glycoprotein (HC-gp39), osteopontin, type IV collagenase, and tryptophanyl-tRNA synthetase] the specific expression in MAC versus MO was previously unknown but could be confirmed by the use of Northern blot analysis [27].
• Oxidative stress-responsive intracellular regulation specific for the angiostatic form of human tryptophanyl-tRNA synthetase [28].
• We herein show that an oxidized form of human glyceraldehyde-3-phosphate dehydrogenase (GapDH) interacts with both full-length and mini TrpRSs and specifically stimulates the aminoacylation potential of mini, but not full-length, TrpRS [28].

Analytical, diagnostic and therapeutic context of WARS

• Mini TrpRS is shown here to be angiostatic in a mammalian cell culture system, the chicken embryo, and two independent angiogenesis assays in the mouse [12].
• Identification of the 53-kDa gamma-IFN-induced protein was confirmed by immunoblotting with an antiserum directed against beef pancreas tryptophanyl-tRNA synthetase [19].
• Gel-retardation assays showed that the acceptor minihelix and the anticodon microhelix were recognized by the domains of TrpRS spanning residues 108-122 and residues 234-238 respectively [29].
• Soubbotitch, Senior Surgeon, Belgrade State Hospital, Serbia (now part of Yugoslavia) and a Lieutenant Colonel in the Serbian Army Reserve during the Balkan Wars (Serbo-Turkish and Serbo-Bulgarian) initiated one of the first clinical programs that emphasized repair, rather than ligation, of injured arteries and veins [30].
• Autoantibodies to highly purified tryptophanyl-tRNA synthetase, consisting of two approximately 60-kDa subunits (6.1.1.2, TrpRS), were detected in some sera of donors and patients with various diagnosis using the newly developed 125I-TrpRS-radiodot, 125I-TrpRS-radioblot, ELISA and Western immunoblotting [31].

References