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Functions Likely (function + likely)
Selected AbstractsFunctional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B,HUMAN MUTATION, Issue 5 2010Leiah M. Luoma Abstract Wilson disease (WND) is an autosomal recessive disorder resulting from mutation of ATP7B. Transport of copper by ATP7B from the trans -Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body. Although copper is an essential nutrient, homeostasis must be carefully maintained. If homeostasis is disrupted, copper can accumulate within the liver, kidney, cornea, and/or brain. The range of organs affected leads to clinical heterogeneity and difficulty in WND diagnosis. Sequencing of ATP7B is an important adjunct for diagnosis but has led to the discovery of many novel missense variants. Although prediction programs are available, functional characterization is essential for determining the consequence of novel variants. We have tested 12 missense variants localized to the ATP loop of ATP7B and compared three predictive programs (SIFT, PolyPhen, and Align-GVGD). We found p.L1043P, p.G1000R, p.G1101R, p.I1102T, p.V1239G, and p.D1267V deleterious; p.G1176E and p.G1287S intermediate; p.E1173G temperature sensitive; p.T991M and p.I1148T mild; and p.R1228T functioning as wild type. We found that SIFT most often agreed with functional data (92%), compared with PolyPhen (83%) and Align-GVGD (67%). We conclude that variants found to negatively affect function likely contribute to the WND phenotype in patients. Hum Mutat 31:569,577, 2010. © 2010 Wiley-Liss, Inc. [source] Lipopolysaccharide binding of the mite allergen Der f 2GENES TO CELLS, Issue 9 2009Saori Ichikawa Lipid-binding properties and/or involvement with host defense are often found in allergen proteins, implying that these intrinsic biological functions likely contribute to the allergenicity of allergens. The group 2 major mite allergens, Der f 2 and Der p 2, show structural homology with MD-2, the lipopolysaccharide (LPS)-binding component of the Toll-like receptor (TLR) 4 signalling complex. Elucidation of the ligand-binding properties of group 2 mite allergens and identification of interaction sites by structural studies are important to explore the relationship between allergenicity and biological function. Here, we report a ligand-fishing approach in which His-tagged Der f 2 was incubated with sonicated stable isotope-labelled Escherichia coli as a potential ligand source, followed by isolation of Der f 2-bound material by a HisTrap column and NMR analysis. We found that Der f 2 binds to LPS with a nanomolar affinity and, using fluorescence and gel filtration assays that LPS binds to Der f 2 in a molar ratio of 1 : 1. We mapped the LPS-binding interface of Der f 2 by NMR perturbation studies, which suggested that LPS binds Der f 2 between the two large ,-sheets, similar to its binding to MD-2, the LPS-binding component of the innate immunity receptor TLR4. [source] CaM kinase II and protein kinase C activations mediate enhancement of long-term potentiation by nefiracetam in the rat hippocampal CA1 regionJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Shigeki Moriguchi Abstract Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as cognitive-enhancing effect. We previously showed that nefiracetam potentiates NMDA-induced currents in cultured rat cortical neurons. To address questions whether nefiracetam affects NMDA receptor-dependent synaptic plasticity in the hippocampus, we assessed effects of nefiracetam on NMDA receptor-dependent long-term potentiation (LTP) by electrophysiology and LTP-induced phosphorylation of synaptic proteins by immunoblotting analysis. Nefiracetam treatment at 1,1000 nM increased the slope of fEPSPs in a dose-dependent manner. The enhancement was associated with increased phosphorylation of ,-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) without affecting synapsin I phosphorylation. In addition, nefiracetam treatment increased PKC, activity in a bell-shaped dose,response curve which peaked at 10 nM, thereby increasing phosphorylation of myristoylated alanine-rich protein kinase C substrate and NMDA receptor. Nefiracetam treatment did not affect protein kinase A activity. Consistent with the bell-shaped PKC, activation, nefiracetam treatment enhanced LTP in the rat hippocampal CA1 region with the same bell-shaped dose,response curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with CaMKII and PKC, activation with concomitant increases in phosphorylation of their endogenous substrates except for synapsin I. These results suggest that nefiracetam potentiates AMPA receptor-mediated fEPSPs through CaMKII activation and enhances NMDA receptor-dependent LTP through potentiation of the post-synaptic CaMKII and protein kinase C activities. Together with potentiation of nicotinic acetylcholine receptor function, nefiracetam-enhanced AMPA and NMDA receptor functions likely contribute to improvement of cognitive function. [source] Rational shaping of liquid crystalline diacylaminophenyl platforms equipped with chelating fragments, fluorescent dyes, and square planar platinum complexesTHE CHEMICAL RECORD, Issue 1 2009Raymond Ziessel Abstract Recent investigations from our laboratory have described compelling experimental evidences that the use of a central 4-methyl-3,5-diacylaminophenyl platform functionalized with two lateral aromatic rings each bearing three appended aliphatic chains is well-suited to produce liquid crystalline materials, some of which carrying at the tips (A-substitution position) chelating fragments such as phenanthroline, terpyridine, alkynyl functions, crown ethers or highly luminescent subunits such as difluoroboradiazaindacene or cationic platinum-terpyridine complexes. An important carvet of this research program is that the presence of amide functions likely stabilizes the mesophases by hydrogen bondings. Judicious grafting of polycatenar tails to the platform insures formation of mesomorphic materials over a large temperature range. Careful design of the system by the direct connection of the platform via alkyne bonds to square planar platinum centers give rise to intriguing phosphorescent metallomesogens. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 1,23; 2009: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20164 [source] | ||||||||||